Abstract
Kainate receptors (KARs) are considered one of the key modulators of synaptic activity in the mammalian central nervous system. These receptors were discovered more than 30 years ago, but their role in brain functioning remains unclear due to some peculiarities. One such feature of these receptors is the editing of pre-mRNAs encoding GluK1 and GluK2 subunits. Despite the long history of studying this phenomenon, numerous questions remain unanswered. This review summarizes the current data about the mechanism and role of pre-mRNA editing of KAR subunits in the mammalian brain and proposes a perspective of future investigations.
Introduction
Kainate receptors are ionotropic glutamate receptors (iGluRs) that localize both pre- and post-synaptically and are involved in synaptic transmission. Activation of postsynaptic KARs evokes low-amplitude excitatory currents (EPSCs) with slow rise and decay kinetics (Pinheiro et al. 2013). It is interesting to note that numerous postsynaptic effects of KARs are mediated by non-canonical metabotropic action (Rodrigues and Lerma 2012), which involves activation of G-proteins, phospholipase C (PLC), and protein kinase C (PKC). KAR-associated downstream metabotropic pathway mediates the suppression of slow afterhyperpolarizing currents (IsAHP) (Melyan et al. 2004), enhancement of synaptic recycling of AMPA receptors, induction of NMDAR-independent long-term potentiation (Petrovic et al. 2017).
The significant presynaptic localization of KARs is assumed to be their distinctive feature allowing them to modulate the secretion of the neurotransmitters, such as glutamate and GABA (Lerma 2003). It was hypothesized that the metabotropic pathway suppresses release (Negrete-Díaz et al. 2018; Rodríguez-Moreno and Lerma 1998; Vignes et al. 1998), whereas the canonic ionotropic pathway, as a rule, enhances secretion (Andrade-Talavera et al. 2013; Jiang et al. 2001; Mathew et al. 2008; Negrete-Díaz et al. 2018) but there are exceptions (Kwon and Castillo 2008). The type of neuron and local agonist concentration may determine which downstream pathway (ionotropic or metabotropic) will be activated (Ruiz et al. 2005), but the KAR subunit requirement for metabotropic activation remains controversial (Fernandes et al. 2009; Ruiz et al. 2005).
As with other iGluRs, KARs are permeable for Na+, but in some cases, these receptors are also permeable for Ca2+. Ca2+-permeability is determined by posttranscriptional editing of mRNA for the GluK1 and GluK2 subunits. A similar mechanism of ion permeability regulation has been reported for AMPARs, but Ca2+ permeability of AMPARs also depends on the subunit composition: GluA2-lacking receptors and receptors containing the unedited GluA2(Q) subunit are Ca2+-permeable (Cull-Candy and Farrant 2021). In addition to Ca2+-permeability, the editing also affects other aspects of KAR functioning that will be discussed further.
Structure and properties of kainate receptors
It has been demonstrated that subunits of NMDARs, AMPARs, and KARs are characterized by moderate homology (Lerma et al. 2001). The structure of KAR subunits is similar to that of other iGluRs subunits and includes (Figure 1): N-terminal/amino-terminal domain (NTD/ATD), C-terminal domain (CTD), ligand-binding domain (LBD), and four hydrophobic domains (M1, M2, M3, M4). M1, M3, and M4 domains are transmembrane, whereas M2 is a re-entrant loop forming part of the channel pore. As with other iGluRs, the glutamate binding site of KAR subunits consists of S1 and S2 segments (Bettler and Mulle 1995; González-González et al. 2012). The S1 segment immediately precedes the first transmembrane helix (M1), while the S2 segment is within the extracellular loop between M3 and M4 (Kristensen et al. 2016).
Structure of kainate receptors. KAR subunits consist of N-terminal/amino-terminal domain (NTD/ATD), C-terminal domain (CTD), ligand-binding domain (LBD), and four hydrophobic domains (M1, M2, M3, M4). LBD includes segments S1 and S2. The subunits combine into dimers (rather heterodimers than homodimers) that form tetramers. GluK4 and GluK5 subunits form functional receptors only in combination with GluK1-3 subunits.
As with AMPAR or NMDAR, KAR is a tetramer forming from different combinations of subunits. GluK1-3 (previously named GluR5-7) subunits can form functional homomeric or heteromeric receptors (Cui and Mayer 1999), while GluK4-5 (previously called KA1 and KA-2) subunits form functional receptors only in combination with GluK1-3 subunits (Herb et al. 1992; Werner et al. 1991). ATD domain plays a pivotal role in the assembly of homomers and heteromers since the formation of dimers begins from the dimerization of ATD domains (Kumar et al. 2011). According to recent molecular modeling studies, heteromeric receptors are formed by two heterodimers rather than homodimers (Khanra et al. 2021; Kristensen et al. 2016; Paramo et al. 2017).
Metal ions, including Zn2+ and Cd2+, modulate the activity of KARs (Blakemore and Trombley 2020; Mott et al. 2008; Wilding and Huettner 2019), but the exact binding sites have not been recognized yet. It was reported that in the case of GluK3 containing heteromers and homomers, Zn2+ may bind with aspartate (Asp759) and histidine (His762) residues in S2 segment (Veran et al. 2012). In turn, the potential sites responsible for the binding of cadmium ions may localize in M3 helix since cysteine substitutions at A657 or L659 positions of GluK2 subunit result in forming Cd2+-binding site. Interestingly, the binding of cadmium ions with the substituted cysteine residues promotes the channel opening in GluK2-containing receptors; however, it cannot be stated that these residues are involved in the binding of Cd2+ in wild-type KARs (Wilding and Huettner 2019).
As with the metal ions, protons and polyamines also modulate the activity of KARs. Extracellular acidification inhibits the currents mediated by KARs, and this effect of protons depends on the subunit composition of the receptor. The mechanism of proton inhibition is unclear, but as proposed, the susceptibility of GluK2 (and possibly GluK1) homomers to protons is mediated by the NTD extracellular site formed by two glutamine residues (E396 and E397) (Mott et al. 2003). Notably, extracellular polyamines modulate the activity of KARs in a pH-dependent manner, reducing the inhibition induced by extracellular acidification. In contrast, endogenous intracellular polyamines, such as spermine, block unedited KARs in a manner similar to inwardly rectifying potassium channels. The introduction of positively charged arginine side chains by editing in the pore loop eliminates polyamine block (Panchenko et al. 2001; Wilding et al. 2010).
Due to some homology of GluK2 (and partially GluK1) subunit sequence to sequence of fatty acid-binding proteins, it was proposed that arachidonic (AA) and docosahexaenoic (DHA) acids can modulate the activity of kainate receptors (Kovalchuk et al. 1994). This hypothesis was further confirmed in the series of works published by Wilding and colleagues (Lopez et al. 2013; Wilding et al. 1998, 2005, 2008, 2010). The authors demonstrated that inhibition of currents through KARs was caused by fatty acids but not by their metabolites and did not involve PKC-mediated signaling (Wilding et al. 1998). Direct binding of DHA may occur in the cavity of the channel, resulting in changes in M3 helix orientation (Wilding et al. 2010).
Recently it has been shown that KAR functions are modulated by auxiliary neuropilin and tolloid-like (NETO) proteins, NETO1 and NETO2, which sequence similarity accounts for 80% (Straub et al. 2011a). NETOs contain two complement C1r/C1s/Uegf/Bmp domains (CUB-domain) and one copy of the cysteine-rich low-density lipoprotein class A (LDLa) modules (Stöhr et al. 2002). NETO1 and NETO2 were found throughout the mammal central nervous system. NETO1 is highly expressed in the cerebral cortex, hippocampus (especially CA3 region), olfactory bulb, olfactory tubercle, and caudate putamen (Michishita et al. 2003; Ng et al. 2009; Straub et al. 2011a). In turn, NETO2 is widely expressed in many brain regions, except the hippocampus (Straub et al. 2011a). Although the interaction of NETOs with NMDARs was suggested in several studies (Cousins et al. 2013), these proteins are considered auxiliary subunits only of KARs (Straub et al. 2011a; Tang et al. 2011), whereas modulation of NMDAR functions by NETOs is indirect (Molnár 2013). KAR-NETO interaction occurs through several sites: NTD-CUB1 interaction and core-NETO interaction involving M3-S2 linker and LBD dimer interface (Griffith and Swanson 2015; Li et al. 2019). NETOs also interact with scaffold KAR-associating protein GRIP and stabilize the complexes of GRIP with KAR subunits. As shown for NETO2, C-terminal domain of NETOs may play a critical role in NETO-GRIP interaction (Tang et al. 2012). Interestingly, Ca2+/calmodulin-dependent protein kinase II (CaMKII) and protein kinase A (PKA) can regulate the activity of NETOs, at least NETO2 (Lomash et al. 2017).
According to the accumulated data, NETOs modulate the activity of postsynaptic KARs (Tang et al. 2011), while their role in the modulation of presynaptic receptors remains to be elucidated. Both NETOs significantly increase GluK1 surface expression and drive GluK1 to synapses (Copits et al. 2011; Sheng et al. 2015), but apparently do not govern GluK2 trafficking (Sheng et al. 2017; Straub et al. 2011a; Zhang et al. 2009). This distinction in trafficking regulation can be determined by the ATD structure of GluK1 and GluK2 subunits (Sheng et al. 2017). However, the conclusion about non-involvement of NETOs in GluK2 trafficking may be true only in the case of the hippocampus since Tang and colleagues reported that NETO2 deficit results in the reduced synaptic expression of GluK2 subunits in the cerebellum (Tang et al. 2012). NETO1-mediated increase in the GluK1 surface expression can elicit neurite elongation in interneurons (Jack et al. 2019) and promote synaptogenesis in CA3-CA1 circuits (Orav et al. 2017).
Numerous studies report that NETOs regulate biophysical properties of GluK1 and GluK2 receptors (Sheng et al. 2017) including glutamate affinity and desensitization kinetics (Palacios-Filardo et al. 2016; Straub et al. 2011a, 2011b; Zhang et al. 2009). NETO1 and NETO2 increase the affinity of GluK1 and GluK2 receptors to glutamate (Fisher 2015; Orav et al. 2017; Palacios-Filardo et al. 2016), while their impact on desensitization seems to be more complex. NETO2 slows desensitization of GluK1, GluK2, GluK1/5, and GluK2/5 receptors in the transfected cells (Straub et al. 2011b; Zhang et al. 2009) and GluK1 receptors in hippocampal neurons (Copits et al. 2011). On the contrary, NETO1 increases the desensitization rate of GluK1 receptors in hippocampal neurons (Copits et al. 2011) and decreases the amplitude of KAR-mediated currents. This effect is not observed in the case of NETO2 deficit, thus indicating its insignificant contribution to the modulation of hippocampal KARs activity (Tang et al. 2011). Interestingly, an inverse correlation has been found in the cerebellum, where NETO1 is expressed only in deep cerebellar nuclei, and the role of this auxiliary protein seems to be negligible (Tang et al. 2012).
Auxiliary proteins decrease inward rectification (IR) of KARs (Brown et al. 2016; Fisher and Mott 2012), facilitating polyamine permeation (Brown et al. 2016), but do not affect Ca2+-permeability (Fisher and Mott 2012). A crucial role in IR regulation plays extracellular LDLa domain of NETOs, which is not involved in the modulation of KAR desensitization (Fisher and Mott 2012). As shown for NETO2, the ability to regulate IR may be explained by the proximity of the NETO2 transmembrane domain to the selectivity filter of KAR and competition with H1 helix for interaction with an intracellular cap domain formed by the M1–M2 linkers (He et al. 2021).
RNA editing is a chemical modification of nucleotides in a molecule of pre-mRNA (Nishikura 2010) that was firstly reported for mRNAs of trypanosomes (Benne et al. 1986) and further demonstrated for mammals. In contrast to splicing, which implies cutting and inserting long sequence fragments, RNA editing is a more delicate process affecting a single nucleotide (Nishikura 2010) (Figure 2). Two variants of this modification have been reported in the human brain: conversion of adenosine to inosine (A/I) and cytidine to uracil (C/U) (Blow et al. 2004). C/U is a rare and poorly studied modification compared to A/I, so we focus on A/I editing in the present review. Since inosine is recognized as guanosine during translation, RNA editing changes the codon meaning, resulting in amino acid replacement in a polypeptide chain. The adenosine to inosine conversion is catalyzed by the enzymes which belong to the family of adenosine deaminases acting on RNA (ADARs) (Barbon and Barlati 2011; Hood and Emeson 2012; Nishikura 2016). Two ADAR isoforms, ADAR1 and ADAR2, are involved in this process in mammalian cells. The structure of the catalytic domain of these two isoforms is similar (Thomas and Beal 2017), while the expression profile of the isoforms in tissues is different (Nishikura 2016). Interestingly, the editing sites are characterized by the selectivity for ADAR isoform (Costa Cruz et al. 2020).
Editing of GluK1 and GluK2 pre-mRNAs. ADAR1 and ADAR2 catalyze adenosine to inosine conversion (A→I). GluK1 and GluK2 pre-mRNAs are edited at Q/R site where A→I change results in replacing glutamine (Q) to arginine (R) in a polypeptide chain. GluK2 pre-mRNA undergoes editing at two additional sites: I/V (isoleucine (I) is replaced by valine (V)) and Y/C (tyrosine (Y) is replaced by cysteine (C)) sites.
Although numerous novel ADAR targets have been found in the genome using the deep sequencing method (Sakurai et al. 2014), only a fraction of these sites is preserved over the course of mammalian evolution (Pinto et al. 2014), whereas other sites of nucleotide change are obviously non-conserved and vary in dependence on the species of a living organism. In this regard, it was proposed that mRNA editing contributes to the adaptability of the organisms affecting transcriptome and proteome but not genome (Gommans et al. 2009). A higher amount of inosine in brain mRNA than in mRNA extracted from other tissues may indicate that the A-to-I editing process is widely spread in the mammalian nervous system, and its role seems to be more complex than anticipated (Paul and Bass 1998). Indeed, analysis of new potential ADAR targets in Drosophila revealed the editing mRNA for voltage-gated channels (sodium, potassium, and calcium channels) and synaptotagmin, a Ca2+ sensor involved in neurotransmission (Hoopengardner et al. 2003). In the case of the mammalian nervous system, mRNA editing has been shown for Cav1.3 channels (Huang et al. 2012), 5-HT2C receptors (Burns et al. 1997), GABA(A) (Daniel et al. 2011), and AMPA receptors (Wright and Vissel 2012). The presence of numerous ADAR targets in the nervous system emphasizes the role of RNA editing in neurotransmission and synaptic plasticity.
The change in nucleotides in GluK1 and GluK2 (Figure 2) resulting from editing was first demonstrated in 1991 in the work of Sommer et al. (Sommer et al. 1991). A-to-I change converts triplet CAG encoding glutamine (Q) to CIG triplet encoding arginine (R), so the site in the polypeptide chain where glutamine to arginine substitution occurs is called the Q/R site. Q/R site is located in re-entrant M2 loop at position 636 in GluK1 and 621 in GluK2 (Köhler et al. 1993; Sailer et al. 1999), between the upstream helix and downstream open coil (Wilding et al. 2008) involved in the formation of the selectivity filter. GluK2 mRNA can also be edited at two additional sites of the transmembrane M1 domain: I/V site (position 567) and Y/C site (position 571). At the I/V site, AUU triplet encoding isoleucine converts to IUU triplet encoding valine, while at the Y/C site, UAC triplet encoding tyrosine converts to UIC triplet encoding cysteine (Egebjerg and Heinemann 1993; Köhler et al. 1993). Although in mature rat or human brain nucleotide changes in GluK3 subunit occur (Lomeli et al. 1992; Nutt et al. 1994), this subunit is not edited. As demonstrated, changing serine to alanine at position 310 of the human GluK3 subunit is caused by bi-allelic polymorphism but not by mRNA editing (Schiffer et al. 2000).
As known, both ADAR isoforms are involved in Q/R editing of GluK1 and GluK2 mRNAs (Nishikura 2016), but ADAR1 edits GluK2 mRNA in mice cortex only in the absence of ADAR2 (Costa Cruz et al. 2020), suggesting that ADAR1 only partially compensates ADAR2 absence (Hideyama and Kwak 2011; Heraud-Farlow et al. 2017; Licht et al. 2019). Moreover, ADAR2 expression in mice brain is higher than ADAR1 expression (Heraud-Farlow et al. 2017), so it may be possible that ADAR2 plays a dominant role in editing kainate receptor subunits (at least GluK2).
Since ADARs recognize only double-stranded regions of RNA, the editing sites are characterized by complementary structure (editing complementary structure/ECS). In GluK1 and GluK2 mRNAs, ECSs are intronic sequences; therefore, the editing of these mRNAs is a co-transcriptional process occurring in a nucleus preceding splicing (Herb et al. 1996) and polyadenylation (Hsiao et al. 2018). The editing of exonic sites with intronic ECSs is controlled by splicing since the negative correlation between editing of sites with intronic ECSs and splicing efficiency has been demonstrated (Licht et al. 2016). A similar correlation has also been shown for GluK1 and GluK2 pre-mRNAs (Licht et al. 2019).
Interestingly, the editing of KAR subunit pre-mRNA has been found in neurons and other brain cells, including astrocytes. Cultured cortical astrocytes predominantly express GluK2-GluK5 mRNA, whereas GluK1 expression is poor (Li et al. 2011). However, the level of Q/R editing of GluK1 and GluK2 pre-mRNA in isolated cortical astrocytes is low. In contrast, oligodendrocyte precursor cells demonstrate a significant level of Q/R and Y/C editing of GluK2 pre-mRNA (Gal-Mark et al. 2017). Although astrocytes express GluK2 containing kainate receptors in cultures and slices (Strutz-Seebohm et al. 2005), GluK2 mRNA editing has been demonstrated in cultures so far (Lowe et al. 1997). Moreover, the editing of GluK2 pre-mRNA in cultured astrocytes occurs only in the case of co-cultivation with neurons, while the editing has not been found in purified cultures of hippocampal astrocytes. Notably, the expression of KAR subunits in astrocytes can increase at some pathologies, for instance, epilepsy (Vargas et al. 2013). In turn, it raises the question of how mRNA editing of the subunits changes under these conditions? However, there are almost no studies regarding this question. It was shown that antidepressant fluoxetine inhibiting serotonin uptake increases expression and editing of GluK2 mRNA in cortical astrocytes, while these changes were not observed in neurons (Li et al. 2012).
Editing of KAR subunits pre-mRNA
The effects of editing on the structure and properties of KARs
GluK1 and GluK2 pre-mRNA editing at the Q/R site in the re-entrant M2 domain enriches the structural diversity of KARs (Lerma and Marques 2013). Editing does not impact the assembly of GluK1/GluK2 heteromers (Cui and Mayer 1999; Paternain et al. 2000). It is also known that the formation of heteromers between GluK2(R) and GluK3 subunits (Perrais et al. 2009; Pinheiro et al. 2007) or between recombinant “edited” GluK3 (site-specific mutagenesis changing Q to R) and non-edited GluK1 (GluK1(Q)) or GluK2 (GluK2(Q)) subunits (Cui and Mayer 1999) is possible.
Replacement of the amino acid decreases the conductance of the receptor (Swanson et al. 1996) and permeability for Ca2+ (Egebjerg and Heinemann 1993; Köhler et al. 1993; Orth et al. 2013). It was suggested in this regard that editing does not change pore diameter, and the differences in Ca2+-permeability may be explained by the redistribution of charge density, creating an energetic barrier for Ca2+ entry (Burnashev et al. 1996). Glutamate-induced currents through homomeric receptors formed by GluK1(R) and GluK2(R) subunits are characterized by lower amplitude compared to the currents through non-edited homomers (Coussen et al. 2005; Sommer et al. 1992; Swanson et al. 1996). However, in the case of GluK1(Q)/GluK2(R) or GluK1(R)/GluK2(Q) heteromers, the amplitudes of currents in response to agonists of GluK1-containing receptors are higher compared to the edited homomers (Cui and Mayer 1999).
Q/R editing affects the modulation of KARs by cadmium ions, polyamines, and fatty acids. The currents through GluK2(R) homomers are more sensitive to inhibition by cadmium ions compared to GluK2(Q) homomers, while the sensitivity to zinc ions does not depend on the editing (Mott et al. 2008). In the case of GluK2/GluK5 heteromers, the editing of GluK2 also does not abolish inhibition by Zn2+ (Fukushima et al. 2003). Furthermore, the editing does not affect inhibition of GluK2(R) homomers by protons but leads to potentiation by polyamines spermine and spermidine in a voltage-independent manner (Mott et al. 2003). In turn, GluK2(R) homomers, in contrast to GluK2(Q) homomers, are significantly inhibited by unsaturated fatty acids such as arachidonic acid (AA) or docosahexaenoic acid (DHA) (Wilding et al. 2005). It is proposed that the susceptibility to fatty acids depends on pore loop conformation (Wilding et al. 2008) since Q/R editing of GluK2 mRNA results in substantial changes in the interaction between pore loop and side chains along an adjacent segment of the M3 helix, and residue 614 is considered to be the most probable site of M3 helix mediating this interaction (Lopez et al. 2013; Wilding et al. 2010). DHA enhances this interaction, especially in the case of the Q/R edited subunits, whereas I/V and Y/C editing of GluK2 mRNA does not affect the susceptibility to DHA.
Different kinases, including PKA, PKC, Src, modulate the activity of iGluRs (Wang et al. 1991, 1994; Zhu et al. 2014). Interestingly, Src kinase increases the activity of GluK2(Q) homomers but does not affect GluK2(R) homomers (Zhu et al. 2014). It raises the question of how editing can affect the ability of other kinases to govern the receptor activity?
Developmental changes in the editing of KAR subunits pre-mRNA
It has been found that GluK1 and GluK2 mRNA editing occurs in almost all brain regions of rats, and the percentage of the edited mRNA increases during the development (Table 1). However, the editing levels of these two mRNAs differ drastically. The portion of the edited GluK2 mRNA in cortex, hippocampus, and cerebellum is more than 70% at the embryonic stage (E19) and achieves approximately 90% in the brain of 2-months rats (Bernard et al. 1999; Paschen et al. 1997). In turn, GluK1 mRNA editing in these brain regions does not exceed 30% at embryonic or early postnatal stages and reaches approximately 50–70% in mature animals (Bernard et al. 1999; Paschen et al. 1995). A similar tendency towards enhancing GluK1 and GluK2 Q/R editing was observed in mice brains during maturation. In addition, I/V and Y/C editing of GluK2 mRNA also increased in this case (Wahlstedt et al. 2009). As regards humans, more than 50% of GluK1 and GluK2 mRNA is edited at Q/R site (Table 1). According to the data presented in Table 1, it can be concluded that the percentage of GluK1-containing Ca2+-permeable KARs in the mature brain (around 50% of edited GluK1 pre-mRNA) is significantly higher than the percentage of GluK2-containing Ca2+-permeable KARs (approximately 90% of edited GluK2 pre-mRNA).
Developmental changes in GluK1 and GluK2 pre-mRNA editing at the Q/R site.
-
Bold and italics are used to discriminate the percentage and ages and improve visualization of the data reported in the table.
The changes in the editing level during the development likely correlate with the expression profile of ADAR2: its expression is low in the embryonic brain and significantly increases during maturation (Behm et al. 2017). It has been reported that ADAR expression and Q/R editing are also affected by learning. For instance, a temporary increase in GluK1(Q) mRNA percentage is observed in the amygdala of animals trained in the trace fear conditioning protocol. Additionally, it was shown that the efficacy of the learning correlates with the level of non-edited mRNA in CA1 field of the hippocampus. Regarding ADARs expression, the experience-dependent changes in ADAR1 and ADAR2 mRNA levels were reported for the hippocampus and amygdala, while a learning-dependent increase of inactive ADAR2 level was found in the amygdala (Brande-Eilat et al. 2015).
Role of the editing
Work on AMPA receptor biosynthesis indicates that unedited GluA2(Q) readily forms homotetramers that are delivered to the plasma membrane (Greger et al. 2003), whereas edited GluA2(R) subunits are largely retained in the endoplasmic reticulum (ER). Similar results were obtained for KARs by Ball and colleagues, who found that editing of GluK2 mRNA at the Q/R site leads to a reduction in endoplasmic reticulum (ER) export and in plasma membrane expression and a decrease in oligomerization of GluK2 with other subunits, causing accumulation of subunit monomers and dimers in the ER (Ball et al. 2010). In contrast, however, the Hollmann lab (Ma-Högemeier et al. 2010), using a similar heterologous expression system (HEK cells), reported efficient oligomerization, ER export, and surface delivery of fluorescently tagged GluK2(R). More recent work in neurons (Evans et al. 2017) supports the idea that native un-tagged edited subunits exhibit deficits in forward trafficking. Evans and colleagues found that chronic depression of neuronal activity with tetrodotoxin in hippocampal cultures leads to a decrease in Q/R editing of GluK2 mRNA, thus promoting the formation of functional KARs and their transport to the plasma membrane (Evans et al. 2017). These data indicate that the Q/R editing of GluK2 mRNA depends on synaptic activity. Interestingly, this correlation is specific for KAR receptors. Although GluA2 subunit of AMPAR is also edited, Q/R editing of GluA2 mRNA is not affected by inhibiting synaptic transmission with tetrodotoxin (blocker of voltage-gated Na+-channels) (Gurung et al. 2018). The proteasomal degradation of ADAR2 is most likely the main cause of a decrease in GluK2 mRNA editing (Gurung et al. 2018). Thus, the data about the effects of Q/R editing on the formation and trafficking of KARs are controversial and require further confirmation.
As known, mRNA editing also affects KAR-mediated presynaptic differentiation. It was reported that expression of the edited and non-edited GluK1 mRNA increased the density of synaptophysin-positive vesicle clusters, and this effect was more pronounced in the case of the non-edited subunit. Expression of GluK1(Q) and GluK2(Q) subunits increases the widening of the active synaptic zone. Moreover, the presence of the non-edited GluK1-3 subunits raises the possibility of glutamate release from presynaptic terminals, indicating the contribution of Ca2+ influx in this process (Sakha et al. 2016). Using cell cultures, it has been demonstrated that activation of the non-edited KARs of DRG neurons does not affect the growth cone area, the number of primary neurites, and the number of branches off the primary neurite but significantly impacts neurite outgrowth. Treatment of cell cultures with KA suppressed the growth of neurites, while antagonists of the Ca2+-permeable receptors used separately or together with kainic acid (KA) stimulated the growth (Joseph et al. 2011). It was reported using avian ciliary ganglion (CG) neurons that the editing of GluK1 mRNA enhances after the formation of peripheral synapses (Olsen et al. 2007). Collectively, these findings suggest that Ca2+ influx through KARs may promote synaptogenesis.
As known, GABAergic neurons demonstrate a specific profile of KAR subunits expression. In particular, it was shown that GABAergic neurons predominantly express GluK1-containing KARs, whereas glutamatergic neurons mainly express GluK2-containing receptors. However, specific populations of neurons can express both GluK1- and GluK2-containing receptors (Mulle et al. 2000; Paternain et al. 2000). Some studies, including our previous works, show that selective agonists of GluK1-containing KARs enhance tonic inhibition in pyramidal neurons (Cossart et al. 1998; Frerking et al. 1998; Khalilov et al. 2002; Maingret et al. 2005; Rodríguez-Moreno et al. 2000; Segerstråle et al. 2010; Semyanov and Kullmann 2001) and suppress network activity (Jack et al. 2019; Khalilov et al. 2002; Kosenkov et al. 2019; Zinchenko et al. 2021) that is caused by activation of interneurons and GABA secretion (Cossart et al. 1998, 2001; Lv et al. 2012; Maingret et al. 2005; Maiorov et al. 2021; Semyanov and Kullmann 2001). It should be noted that modulation of interneurons excitability (enhance of firing) by GluK1-containing KARs is strongly downregulated during maturation (Segerstråle et al. 2010), and only a fraction of interneurons in the adult hippocampus undergo modulation by GluK1 agonists (Cossart et al. 1998). According to Table 1, about 50% of GluK1 mRNA is edited at the Q/R site in the adult hippocampus, suggesting that approximately half of GluK1-containing KARs may be Ca2+-permeable (non-edited). In keeping with this, it can be assumed that GluK1-containing Ca2+-permeable KARs contribute to modulation of interneurons firing and tonic GABA secretion. Hippocampal GABAergic neurons containing Ca2+-permeable KARs demonstrate higher excitability that can be explained by insufficient GABA(A)R inhibition in these cells (Kosenkov et al. 2019; Zinchenko et al. 2017). This peculiarity in addition to the presence of Ca2+-permeable KARs, which activation directly modulate GABA release due to additional Ca2+ inflow in presynaptic terminal, allows them react to depolarizing stimuli earlier and prevent overexcitation of the innervated neurons. Taken together, it can be assumed that interneurons with constitutive expression of Ca2+-permeable KARs may fulfill an important role in tuning excitation/inhibition balance.
The level of mRNA editing and, therefore, Ca2+-permeability of KARs contribute to long-term potentiation and synaptic facilitation. Using mice deficient in GluK2 Q/R site editing, it has been shown that KARs containing GluK2(Q) subunit can mediate NMDAR-independent long-term potentiation at medial perforant path-dentate gyrus synapses. At the same time, a deficit in GluK2 Q/R site editing increases Ca2+ conductance and affects current-voltage characteristics of neuronal KARs. Neurons from mutant mice were characterized by rectifying kainate receptor responses, while kainate receptor current-voltage characteristic was linear in neurons of control mice (Vissel et al. 2001). Furthermore, Ca2+-permeable KARs containing GluK1(Q) subunit contribute to synaptic facilitation that occurs during high-frequency stimulation of mossy fibers (Dargan et al. 2009; Lauri et al. 2003; Scott et al. 2008). Blockade of Ca2+-permeable GluK1-containing KARs decreased short-term facilitation of presynaptic Ca2+ transients in individual mossy fiber boutons. It is supposed that Ca2+ influx through KARs induces mobilization of Ca2+ from intracellular stores, activating signaling cascades that affect short-term and long-term plasticity. Ca2+-permeable KARs also affect short-term facilitation at Schaffer collateral synapses onto SOM interneurons (Sun et al. 2009) since the application of NASPM or Philanthotoxin-433 (antagonists of Ca2+-permeable AMPARs and KARs) decreases paired-pulse facilitation at short intervals. It is noteworthy that the facilitation is caused by presynaptic Ca2+-permeable KARs receptors since the authors observed no change in the size of the first EPSC in the presence of NASPM. However, the type of KARs (GluK1- or GluK2-containing) involved in Ca2+ influx underlying this effect and the exact mechanism of the observed phenomena remain to be elucidated.
The form of LTP resulting from paired-pulse stimulation and requiring Ca2+ influx through presynaptic GluK1-containing receptors was revealed in thalamic input to the lateral nucleus of the amygdala (Shin et al. 2010). A selective agonist of GluK1-containing KARs, ATPA, mimicked this effect. However, paired-pulse stimulation did not induce LTP in the cortico-amygdala pathway, indicating a pathway-dependent manner of this Ca2+-permeable KARs-mediated LTP form. In turn, input timing-dependent plasticity (ITDP) was found in cortical inputs to the lateral nucleus of the amygdala (Cho et al. 2011). This kind of plasticity depends on Ca2+ influx through postsynaptic GluK1-containing Ca2+-permeable receptors and InsP3-sensitive Ca2+ release from internal stores mediated by group I mGluRs activation. Interestingly, induction of ITDP could be reached when both sources of postsynaptic Ca2+ are simultaneously recruited. In the cerebellum, the contribution of Ca2+-permeable KARs in the facilitation of synaptic transmission was found at parallel fibers-Purkinje cells (PF-PuC) synapses. In this case, KAR-mediated Ca2+ entry triggers Ca2+-induced Ca2+ release from intracellular stores to produce synaptic facilitation (Falcón-Moya et al. 2018). In the anterior cingulate cortex (layer II/III), Ca2+ influx through GluK1-containing receptors induces a presynaptic LTP via activation of downstream adenylyl cyclase-PKA cascade, which modulates the activity of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and promotes glutamate release (Koga et al. 2015).
GluK1 and GluK2 pre-mRNA editing in pathologies
Numerous studies have shown that the percentage of the edited and non-edited KAR subunits may determine the susceptibility to different pathological conditions. Regarding epilepsy, it was demonstrated that the edited GluK1 and GluK2 mRNA level was higher in the temporal cortex of epileptic patients than in the control group; however, similar differences were not observed in the hippocampus (Kortenbruck et al. 2001). On the contrary, according to another study, the hippocampi of patients with epilepsy demonstrate an increased level of GluK2 pre-mRNA editing, and these changes correlate with increased expression of ADAR2 (Grigorenko et al. 1998). It remains unknown whether these differences in editing level are inherent or result from adaptive processes aimed to prevent Ca2+ overload in models of epilepsy (Gaidin et al. 2019). Although disturbances of GluK2 Q/R editing increase the vulnerability of the animals to kainate-induced seizures, behavioral tests did not reveal significant changes compared to wild-type mice (Vissel et al. 2001). Moreover, significant developmental or behavioral abnormalities were not observed in animals expressing only the edited or non-edited GluK1 subunit (Sailer et al. 1999). Interestingly, a ketogenic diet that is considered an efficient treatment option for patients with epilepsy leads to an increase in the blood level of unsaturated fatty acids such as docosahexaenoic and arachidonic acids. These acids, as was mentioned above, can inhibit KARs containing the GluK2(R) subunit (Wilding et al. 1998). It has been reported that the ketogenic diet enhances the expression of GluK2 subunit in animals with the developed status epilepticus; however, the level of the edited GluK1 and GluK2 subunits remains unchanged in this case (Xu et al. 2008). In summary, an increase in the percentage of Ca2+-permeable KARs enhances vulnerability to epilepsy, but this change does not substantially affect normal brain functioning.
As hypothesized, a decrease in the number of Ca2+-permeable receptors is one of the adaptive mechanisms of neurons against Ca2+ overload during ischemia. The data obtained in the four-vessel occlusion (4-VO) model of transient forebrain ischemia confirms this hypothesis. GluK1 mRNA editing was enhanced in the striatum 4 h after recovery and maintained at a high level even 24 h after, whereas no changes were observed in the cortex and hippocampus. In turn, the level of GluK2 mRNA editing decreased in all the studied brain regions, but these changes accounted for 10%, indicating that the portion of the edited GluK2 mRNA was significantly higher (∼80%) (Paschen et al. 1996). Interestingly, the opposite changes have been found in the case of acute spinal cord injury (SCI). Caracciolo and colleagues demonstrated a decrease in Q/R editing of GluK1 and GluK2 mRNA being persisted 30 days after the injury (Caracciolo et al. 2013). A similar tendency was shown for I/V and Y/C editing of GluK2 mRNA, and the authors associated these effects with ADAR2 inactivation, which occurs due to injury-induced inflammation (Di Narzo et al. 2015). The editing attenuation promotes the activation of ascending neurons and the propagation of sensory/nociceptive information from the spinal cord to higher brain centers.
The data about the effects of KAR editing on psychical disorders such as schizophrenia are controversial. Lyddon and colleagues found no correlation between glutamate receptor editing and bipolar disorder, schizophrenia or suicide (Lyddon et al. 2012). However, it was shown in more recent work that ADAR2 expression decreased in patients with schizophrenia and bipolar disorder, and this decrease correlated with the reduced editing of R/G site in AMPAR subunits mRNA (Kubota-Sakashita et al. 2014). In other work, increased expression of ADAR1p110 isoform and the elevated level of total ADAR2 and ADAR3 were demonstrated (Silberberg et al. 2012). However, the increase in the level of ADAR2 is driven by increased expression of ADAR2 transcript with Alu insert and deficient ADAR2 (enzymes with the reduced catalytic activity). ADARs expression, Q/R and Y/C editing were not altered in patients with bipolar disorder, whereas I/V editing of GluK2 mRNA was low. Interestingly, I/V editing allows fine-tuning of Ca2+-permeability of GluK2(Q)-containing KARs (Köhler et al. 1993). Chronic treatment of rats with phencyclidine, which induces a form of psychosis mimicking naturally occurring schizophrenia, led to a decrease in GluK1 and GluK2 mRNA levels in the prefrontal cortex but not in the hippocampus (Barbon et al. 2007). Along with these changes, an increase in GluK2 mRNA editing in Q/R site was observed. However, the chronic treatment did not affect ADAR1 and ADAR2 expression, Q/R editing of GluK1 mRNA, and I/V or Y/C editing of GluK2 mRNA. No significant changes in expression and editing were observed in the case of acute phencyclidine treatment.
Conclusions
Altogether, the large body of experimental facts about GluK1 and GluK2 pre-mRNA editing mechanisms and the effects of editing on biophysical properties of the receptors have been accumulated. However, most of the data has been obtained in cellular expression systems such as HEK 293 or oocytes, so it remains uncertain what role GluK1 and GluK2 pre-mRNA editing plays in regulating the activity of neuronal ensembles in the brain. Although GluK1 and GluK2 editing levels vary in different brain regions, in contrast to GluA2 subunit of AMPA receptors, the portion of the edited mRNA in the case of KAR subunits does not reach 100%. As a rule, the homogenates of brain tissues are used to analyze brain mRNA editing. Considering the significant heterogeneity of neurons and the possible expression of KAR subunits by glial cells, we may raise the question of which types of cells demonstrate the more intensive editing of KAR subunits and which physiological changes result from the editing. Moreover, as mentioned above, GluK1 and GluK2 expression profiles depend on the type of neurons. This correlation between the type of neurons and the profile of expression of KAR subunits raises the question of whether the subunits are completely edited in some neurons and not edited in others or whether one neuron simultaneously contains a significant fraction of both edited and unedited subunits. We suppose that these denoted issues should be addressed in future research in this field.
Award Identifier / Grant number: AAAA-A20-120101390067-0
Acknowledgments
This study was conducted in the framework of the State assignment of PSCBR RAS, Project AAAA-A20-120101390067-0.
-
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
-
Research funding: None declared.
-
Conflict of interest statement: None declared.
References
Andrade-Talavera, Y., Duque-Feria, P., Sihra, T.S., and Rodríguez-Moreno, A. (2013). Pre-synaptic kainate receptor-mediated facilitation of glutamate release involves PKA and Ca(2+) -calmodulin at thalamocortical synapses. J. Neurochem. 126: 565–578, https://doi.org/10.1111/jnc.12310.Search in Google Scholar
Ball, S.M., Atlason, P.T., Shittu-Balogun, O.O., and Molnár, E. (2010). Assembly and intracellular distribution of kainate receptors is determined by RNA editing and subunit composition. J. Neurochem. 114: 1805–1818, https://doi.org/10.1111/j.1471-4159.2010.06895.x.Search in Google Scholar
Barbon, A. and Barlati, S. (2011). Glutamate receptor RNA editing in health and disease. Biochemistry (Mosc.) 76: 882–889, https://doi.org/10.1134/s0006297911080037.Search in Google Scholar
Barbon, A., Fumagalli, F., La Via, L., Caracciolo, L., Racagni, G., Riva, M.A., and Barlati, S. (2007). Chronic phencyclidine administration reduces the expression and editing of specific glutamate receptors in rat prefrontal cortex. Exp. Neurol. 208: 54–62, https://doi.org/10.1016/j.expneurol.2007.07.009.Search in Google Scholar
Barbon, A., Vallini, I., La Via, L., Marchina, E., and Barlati, S. (2003). Glutamate receptor RNA editing: a molecular analysis of GluR2, GluR5 and GluR6 in human brain tissues and in NT2 cells following in vitro neural differentiation. Brain Res. Mol Brain Res. 117: 168–178, https://doi.org/10.1016/s0169-328x(03)00317-6.Search in Google Scholar
Behm, M., Wahlstedt, H., Widmark, A., Eriksson, M., and Öhman, M. (2017). Accumulation of nuclear ADAR2 regulates adenosine-to-inosine RNA editing during neuronal development. J. Cell Sci. 130: 745–753, https://doi.org/10.1242/jcs.200055.Search in Google Scholar
Benne, R., van den Burg, J., Brakenhoff, J.P.J., Sloof, P., van Boom, J.H., and Tromp, M.C. (1986). Major transcript of the frameshifted coxll gene from trypanosome mitochondria contains four nucleotides that are not encoded in the DNA. Cell 46: 819–826, https://doi.org/10.1016/0092-8674(86)90063-2.Search in Google Scholar
Bernard, A., Ferhat, L., Dessi, F., Charton, G., Represa, A., Ben-Ari, Y., and Khrestchatisky, M. (1999). Q/R editing of the rat GluR5 and GluR6 kainate receptors in vivo and in vitro: evidence for independent developmental, pathological and cellular regulation. Eur. J. Neurosci. 11: 604–616, https://doi.org/10.1046/j.1460-9568.1999.00479.x.Search in Google Scholar
Bettler, B. and Mulle, C. (1995). AMPA and kainate receptors. Neuropharmacology 34: 123–139, https://doi.org/10.1016/0028-3908(94)00141-e.Search in Google Scholar
Blakemore, L.J. and Trombley, P.Q. (2020). Zinc modulates olfactory bulb kainate receptors. Neuroscience 428: 252–268, https://doi.org/10.1016/j.neuroscience.2019.11.041.Search in Google Scholar PubMed PubMed Central
Blow, M., Futreal, P.A., Wooster, R., and Stratton, M.R. (2004). A survey of RNA editing in human brain. Genome Res. 14: 2379–2387, https://doi.org/10.1101/gr.2951204.Search in Google Scholar
Brande-Eilat, N., Golumbic, Y.N., Zaidan, H., and Gaisler-Salomon, I. (2015). Acquisition of conditioned fear is followed by region-specific changes in RNA editing of glutamate receptors. Stress 18: 309–318, https://doi.org/10.3109/10253890.2015.1073254.Search in Google Scholar
Brown, P.M.G.E., Aurousseau, M.R.P., Musgaard, M., Biggin, P.C., and Bowie, D. (2016). Kainate receptor pore-forming and auxiliary subunits regulate channel block by a novel mechanism. J. Physiol. 594: 1821–1840, https://doi.org/10.1113/jp271690.Search in Google Scholar
Burnashev, N., Villarroel, A., and Sakmann, B. (1996). Dimensions and ion selectivity of recombinant AMPA and kainate receptor channels and their dependence on Q/R site residues. J. Physiol. 496: 165–173, https://doi.org/10.1113/jphysiol.1996.sp021674.Search in Google Scholar
Burns, C.M., Chu, H., Rueter, S.M., Hutchinson, L.K., Canton, H., Sanders-Bush, E., and Emeson, R.B. (1997). Regulation of serotonin-2C receptor G-protein coupling by RNA editing. Nature 387: 303–308, https://doi.org/10.1038/387303a0.Search in Google Scholar
Caracciolo, L., Fumagalli, F., Carelli, S., Madaschi, L., La Via, L., Bonini, D., Fiorentini, C., Barlati, S., Gorio, A., and Barbon, A. (2013). Kainate receptor RNA editing is markedly altered by acute spinal cord injury. J. Mol. Neurosci. 51: 903–910, https://doi.org/10.1007/s12031-013-0098-1.Search in Google Scholar
Cho, J.-H., Bayazitov, I.T., Meloni, E.G., Myers, K.M., Carlezon, W.A., Zakharenko, S.S., and Bolshakov, V.Y. (2011). Coactivation of thalamic and cortical pathways induces input timing-dependent plasticity in amygdala. Nat. Neurosci. 15: 113–122, https://doi.org/10.1038/nn.2993.Search in Google Scholar
Copits, B.A., Robbins, J.S., Frausto, S., and Swanson, G.T. (2011). Synaptic targeting and functional modulation of GluK1 kainate receptors by the auxiliary neuropilin and tolloid-like (NETO) proteins. J. Neurosci. 31: 7334–7340, https://doi.org/10.1523/jneurosci.0100-11.2011.Search in Google Scholar
Cossart, R., Esclapez, M., Hirsch, J.C., Bernard, C., and Ben-Ari, Y. (1998). GluR5 kainate receptor activation in interneurons increases tonic inhibition of pyramidal cells. Nat. Neurosci. 1: 470–478, https://doi.org/10.1038/2185.Search in Google Scholar
Cossart, R., Tyzio, R., Dinocourt, C., Esclapez, M., Hirsch, J.C., Ben-Ari, Y., and Bernard, C. (2001). Presynaptic kainate receptors that enhance the release of GABA on CA1 hippocampal interneurons. Neuron 29: 497–508, https://doi.org/10.1016/s0896-6273(01)00221-5.Search in Google Scholar
Costa Cruz, P.H., Kato, Y., Nakahama, T., Shibuya, T., and Kawahara, Y. (2020). A comparative analysis of ADAR mutant mice reveals site-specific regulation of RNA editing. RNA 26: 454–469, https://doi.org/10.1261/rna.072728.119.Search in Google Scholar PubMed PubMed Central
Cousins, S.L., Innocent, N., and Stephenson, F.A. (2013). Neto1 associates with the NMDA receptor/amyloid precursor protein complex. J. Neurochem. 126: 554–564, https://doi.org/10.1111/jnc.12280.Search in Google Scholar PubMed
Coussen, F., Perrais, D., Jaskolski, F., Sachidhanandam, S., Normand, E., Bockaert, J., Marin, P., and Mulle, C. (2005). Co-assembly of two GluR6 kainate receptor splice variants within a functional protein complex. Neuron 47: 555–566, https://doi.org/10.1016/j.neuron.2005.06.033.Search in Google Scholar PubMed
Cui, C. and Mayer, M.L. (1999). Heteromeric kainate receptors formed by the coassembly of GluR5, GluR6, and GluR7. J. Neurosci. 19: 8281–8291, https://doi.org/10.1523/jneurosci.19-19-08281.1999.Search in Google Scholar
Cull-Candy, S.G. and Farrant, M. (2021). Ca2+ -permeable AMPA receptors and their auxiliary subunits in synaptic plasticity and disease. J. Physiol. 599: 2655–2671, https://doi.org/10.1113/JP279029.Search in Google Scholar PubMed PubMed Central
Daniel, C., Wahlstedt, H., Ohlson, J., Björk, P., and Ohman, M. (2011). Adenosine-to-inosine RNA editing affects trafficking of the gamma-aminobutyric acid type A (GABA(A)) receptor. J. Biol. Chem. 286: 2031–2040, https://doi.org/10.1074/jbc.m110.130096.Search in Google Scholar
Dargan, S.L., Clarke, V.R.J., Alushin, G.M., Sherwood, J.L., Nisticò, R., Bortolotto, Z.A., Ogden, A.M., Bleakman, D., Doherty, A.J., Lodge, D., et al.. (2009). ACET is a highly potent and specific kainate receptor antagonist: characterisation and effects on hippocampal mossy fibre function. Neuropharmacology 56: 121–130, https://doi.org/10.1016/j.neuropharm.2008.08.016.Search in Google Scholar PubMed PubMed Central
Di Narzo, A.F., Kozlenkov, A., Ge, Y., Zhang, B., Sanelli, L., May, Z., Li, Y., Fouad, K., Cardozo, C., Koonin, E.V., et al.. (2015). Decrease of mRNA editing after spinal cord injury is caused by down-regulation of ADAR2 that is triggered by inflammatory response. Sci. Rep. 5: 12615, https://doi.org/10.1038/srep12615.Search in Google Scholar PubMed PubMed Central
Egebjerg, J. and Heinemann, S.F. (1993). Ca2+ permeability of unedited and edited versions of the kainate selective glutamate receptor GluR6. Proc. Natl. Acad. Sci. U. S. A. 90: 755–759, https://doi.org/10.1073/pnas.90.2.755.Search in Google Scholar PubMed PubMed Central
Evans, A.J., Gurung, S., Wilkinson, K.A., Stephens, D.J., and Henley, J.M. (2017). Assembly, secretory pathway trafficking, and surface delivery of kainate receptors is regulated by neuronal activity. Cell Rep. 19: 2613–2626, https://doi.org/10.1016/j.celrep.2017.06.001.Search in Google Scholar PubMed PubMed Central
Falcón-Moya, R., Losada-Ruiz, P., Sihra, T.S., and Rodríguez-Moreno, A. (2018). Cerebellar kainate receptor-mediated facilitation of glutamate release requires Ca2+-calmodulin and PKA. Front. Mol. Neurosci. 11: 195.10.3389/fnmol.2018.00195Search in Google Scholar
Fernandes, H.B., Catches, J.S., Petralia, R.S., Copits, B.A., Xu, J., Russell, T.A., Swanson, G.T., and Contractor, A. (2009). High-affinity kainate receptor subunits are necessary for ionotropic but not metabotropic signaling. Neuron 63: 818–829, https://doi.org/10.1016/j.neuron.2009.08.010.Search in Google Scholar
Fisher, J.L. (2015). The auxiliary subunits Neto1 and Neto2 have distinct, subunit-dependent effects at recombinant GluK1- and GluK2-containing kainate receptors. Neuropharmacology 99: 471–480, https://doi.org/10.1016/j.neuropharm.2015.08.018.Search in Google Scholar
Fisher, J.L. and Mott, D.D. (2012). The auxiliary subunits Neto1 and Neto2 reduce voltage-dependent inhibition of recombinant kainate receptors. J. Neurosci. 32: 12928–12933, https://doi.org/10.1523/jneurosci.2211-12.2012.Search in Google Scholar
Frerking, M., Malenka, R.C., and Nicoll, R.A. (1998). Synaptic activation of kainate receptors on hippocampal interneurons. Nat. Neurosci. 1: 479–486, https://doi.org/10.1038/2194.Search in Google Scholar
Fukushima, T., Shingai, R., Ogurusu, T., and Ichinose, M. (2003). Inhibition of willardiine-induced currents through rat GluR6/KA-2 kainate receptor channels by Zinc and other divalent cations. Neurosci. Lett. 349: 107–110, https://doi.org/10.1016/s0304-3940(03)00805-x.Search in Google Scholar
Gaidin, S.G., Zinchenko, V.P., Teplov, I.Y., Tuleukhanov, S.T., and Kosenkov, A.M. (2019). Epileptiform activity promotes decreasing of Ca2+ conductivity of NMDARs, AMPARs, KARs, and voltage-gated calcium channels in Mg2+-free model. Epilepsy Res. 158: 106224, https://doi.org/10.1016/j.eplepsyres.2019.106224.Search in Google Scholar PubMed
Gal-Mark, N., Shallev, L., Sweetat, S., Barak, M., Billy Li, J., Levanon, E.Y., Eisenberg, E., and Behar, O. (2017). Abnormalities in A-to-I RNA editing patterns in CNS injuries correlate with dynamic changes in cell type composition. Sci. Rep. 7: 43421, https://doi.org/10.1038/srep43421.Search in Google Scholar PubMed PubMed Central
Gommans, W.M., Mullen, S.P., and Maas, S. (2009). RNA editing: a driving force for adaptive evolution? Bioessays 31: 1137–1145, https://doi.org/10.1002/bies.200900045.Search in Google Scholar PubMed PubMed Central
González-González, I.M., Konopacki, F.A., Rocca, D.L., Doherty, A.J., Jaafari, N., Wilkinson, K.A., and Henley, J.M. (2012). Kainate receptor trafficking. WIREs Membr. Transp. Signal 1: 31–44.10.1002/wmts.23Search in Google Scholar
Greger, I.H., Khatri, L., Kong, X., and Ziff, E.B. (2003). AMPA receptor tetramerization is mediated by Q/R editing. Neuron 40: 763–774, https://doi.org/10.1016/s0896-6273(03)00668-8.Search in Google Scholar
Griffith, T.N. and Swanson, G.T. (2015). Identification of critical functional determinants of kainate receptor modulation by auxiliary protein Neto2. J. Physiol. 593: 4815–4833, https://doi.org/10.1113/jp271103.Search in Google Scholar
Grigorenko, E.V., Bell, W.L., Glazier, S., Pons, T., and Deadwyler, S. (1998). Editing status at the Q/R site of the GluR2 and GluR6 glutamate receptor subunits in the surgically excised hippocampus of patients with refractory epilepsy. Neuroreport 9: 2219–2224, https://doi.org/10.1097/00001756-199807130-00013.Search in Google Scholar
Gurung, S., Evans, A.J., Wilkinson, K.A., and Henley, J.M. (2018). ADAR2-mediated Q/R editing of GluK2 regulates kainate receptor upscaling in response to suppression of synaptic activity. J. Cell Sci. 131, https://doi.org/10.1242/jcs.222273.Search in Google Scholar
He, L., Sun, J., Gao, Y., Li, B., Wang, Y., Dong, Y., An, W., Li, H., Yang, B., Ge, Y., et al.. (2021). Kainate receptor modulation by NETO2. Nature 599: 325–329, https://doi.org/10.1038/s41586-021-03936-y.Search in Google Scholar
Heraud-Farlow, J.E., Chalk, A.M., Linder, S.E., Li, Q., Taylor, S., White, J.M., Pang, L., Liddicoat, B.J., Gupte, A., Li, J.B., et al.. (2017). Protein recoding by ADAR1-mediated RNA editing is not essential for normal development and homeostasis. Genome Biol. 18: 166, https://doi.org/10.1186/s13059-017-1301-4.Search in Google Scholar
Herb, A., Burnashev, N., Werner, P., Sakmann, B., Wisden, W., and Seeburg, P.H. (1992). The KA-2 subunit of excitatory amino acid receptors shows widespread expression in brain and forms ion channels with distantly related subunits. Neuron 8: 775–785, https://doi.org/10.1016/0896-6273(92)90098-x.Search in Google Scholar
Herb, A., Higuchi, M., Sprengel, R., and Seeburg, P.H. (1996). Q/R site editing in kainate receptor GluR5 and GluR6 pre-mRNAs requires distant intronic sequences. Proc. Natl. Acad. Sci. U. S. A. 93: 1875–1880, https://doi.org/10.1073/pnas.93.5.1875.Search in Google Scholar PubMed PubMed Central
Hideyama, T. and Kwak, S. (2011). When does ALS start? ADAR2-GluA2 hypothesis for the etiology of sporadic ALS. Front. Mol. Neurosci. 4: 33, https://doi.org/10.3389/fnmol.2011.00033.Search in Google Scholar PubMed PubMed Central
Hood, J.L. and Emeson, R.B. (2012). Editing of neurotransmitter receptor and ion channel RNAs in the nervous system. Curr. Top. Microbiol. Immunol. 353: 61–90, https://doi.org/10.1007/82_2011_157.Search in Google Scholar PubMed PubMed Central
Hoopengardner, B., Bhalla, T., Staber, C., and Reenan, R. (2003). Nervous system targets of RNA editing identified by comparative genomics. Science 301: 832–836, https://doi.org/10.1126/science.1086763.Search in Google Scholar
Hsiao, Y.-H.E., Bahn, J.H., Yang, Y., Lin, X., Tran, S., Yang, E.-W., Quinones-Valdez, G., and Xiao, X. (2018). RNA editing in nascent RNA affects pre-mRNA splicing. Genome Res. 28: 812–823, https://doi.org/10.1101/gr.231209.117.Search in Google Scholar
Huang, H., Tan, B.Z., Shen, Y., Tao, J., Jiang, F., Sung, Y.Y., Ng, C.K., Raida, M., Köhr, G., Higuchi, M., et al.. (2012). RNA editing of the IQ domain in Ca(v)1.3 channels modulates their Ca2⁺-dependent inactivation. Neuron 73: 304–316, https://doi.org/10.1016/j.neuron.2011.11.022.Search in Google Scholar
Jack, A., Hamad, M.I.K., Gonda, S., Gralla, S., Pahl, S., Hollmann, M., and Wahle, P. (2019). Development of cortical pyramidal cell and interneuronal dendrites: a role for kainate receptor subunits and NETO1. Mol. Neurobiol. 56: 4960–4979, https://doi.org/10.1007/s12035-018-1414-0.Search in Google Scholar
Jiang, L., Xu, J., Nedergaard, M., and Kang, J. (2001). A kainate receptor increases the efficacy of GABAergic synapses. Neuron 30: 503–513, https://doi.org/10.1016/s0896-6273(01)00298-7.Search in Google Scholar
Joseph, D.J., Williams, D.J., and MacDermott, A.B. (2011). Modulation of neurite outgrowth by activation of calcium-permeable kainate receptors expressed by rat nociceptive-like dorsal root ganglion neurons. Dev. Neurobiol. 71: 818–835, https://doi.org/10.1002/dneu.20906.Search in Google Scholar
Khalilov, I., Hirsch, J., Cossart, R., and Ben-Ari, Y. (2002). Paradoxical anti-epileptic effects of a GluR5 agonist of kainate receptors. J. Neurophysiol. 88: 523–527, https://doi.org/10.1152/jn.2002.88.1.523.Search in Google Scholar
Khanra, N., Brown, P.M., Perozzo, A.M., Bowie, D., and Meyerson, J.R. (2021). Architecture and structural dynamics of the heteromeric GluK2/K5 kainate receptor. Elife 10, https://doi.org/10.7554/eLife.66097.Search in Google Scholar
Koga, K., Descalzi, G., Chen, T., Ko, H.-G., Lu, J., Li, S., Son, J., Kim, T., Kwak, C., Huganir, R.L., et al.. (2015). Coexistence of two forms of LTP in ACC provides a synaptic mechanism for the interactions between anxiety and chronic pain. Neuron 85: 377–389, https://doi.org/10.1016/j.neuron.2014.12.021.Search in Google Scholar
Köhler, M., Burnashev, N., Sakmann, B., and Seeburg, P.H. (1993). Determinants of Ca2+ permeability in both TM1 and TM2 of high affinity kainate receptor channels: diversity by RNA editing. Neuron 10: 491–500, https://doi.org/10.1016/0896-6273(93)90336-p.Search in Google Scholar
Kortenbruck, G., Berger, E., Speckmann, E.J., and Musshoff, U. (2001). RNA editing at the Q/R site for the glutamate receptor subunits GLUR2, GLUR5, and GLUR6 in hippocampus and temporal cortex from epileptic patients. Neurobiol. Dis. 8: 459–468, https://doi.org/10.1006/nbdi.2001.0394.Search in Google Scholar
Kosenkov, A.M., Teplov, I.Y., Sergeev, A.I., Maiorov, S.A., Zinchenko, V.P., and Gaidin, S.G. (2019). Domoic acid suppresses hyperexcitation in the network due to activation of kainate receptors of GABAergic neurons. Arch. Biochem. Biophys. 671: 52–61, https://doi.org/10.1016/j.abb.2019.06.004.Search in Google Scholar
Kovalchuk, Y., Miller, B., Sarantis, M., and Attwell, D. (1994). Arachidonic acid depresses non-NMDA receptor currents. Brain Res. 643: 287–295, https://doi.org/10.1016/0006-8993(94)90035-3.Search in Google Scholar
Kristensen, O., Kristensen, L.B., Møllerud, S., Frydenvang, K., Pickering, D.S., and Kastrup, J.S. (2016). The structure of a high-affinity kainate receptor: GluK4 ligand-binding domain crystallized with kainate. Structure 24: 1582–1589, https://doi.org/10.1016/j.str.2016.06.019.Search in Google Scholar
Kubota-Sakashita, M., Iwamoto, K., Bundo, M., and Kato, T. (2014). A role of ADAR2 and RNA editing of glutamate receptors in mood disorders and schizophrenia. Mol. Brain 7: 5, https://doi.org/10.1186/1756-6606-7-5.Search in Google Scholar
Kumar, J., Schuck, P., and Mayer, M.L. (2011). Structure and assembly mechanism for heteromeric kainate receptors. Neuron 71: 319–331, https://doi.org/10.1016/j.neuron.2011.05.038.Search in Google Scholar
Kwon, H.-B. and Castillo, P.E. (2008). Long-term potentiation selectively expressed by NMDA receptors at hippocampal mossy fiber synapses. Neuron 57: 108–120, https://doi.org/10.1016/j.neuron.2007.11.024.Search in Google Scholar
Lauri, S.E., Bortolotto, Z.A., Nistico, R., Bleakman, D., Ornstein, P.L., Lodge, D., Isaac, J.T.R., and Collingridge, G.L. (2003). A role for Ca2+ stores in kainate receptor-dependent synaptic facilitation and LTP at mossy fiber synapses in the Hippocampus. Neuron 39: 327–341, https://doi.org/10.1016/s0896-6273(03)00369-6.Search in Google Scholar
Lee, C.J., Kong, H., Manzini, M.C., Albuquerque, C., Chao, M.V., and MacDermott, A.B. (2001). Kainate receptors expressed by a subpopulation of developing nociceptors rapidly switch from high to low Ca 2+ permeability. J. Neurosci. 21: 4572–4581, https://doi.org/10.1523/jneurosci.21-13-04572.2001.Search in Google Scholar
Lerma, J. (2003). Roles and rules of kainate receptors in synaptic transmission. Nat. Rev. Neurosci. 4: 481–495, https://doi.org/10.1038/nrn1118.Search in Google Scholar PubMed
Lerma, J. and Marques, J.M. (2013). Kainate receptors in health and disease. Neuron 80: 292–311, https://doi.org/10.1016/j.neuron.2013.09.045.Search in Google Scholar
Lerma, J., Paternain, A.V., Rodríguez-Moreno, A., and López-García, J.C. (2001). Molecular physiology of kainate receptors. Physiol. Rev. 81: 971–998, https://doi.org/10.1152/physrev.2001.81.3.971.Search in Google Scholar
Li, B., Dong, L., Wang, B., Cai, L., Jiang, N., and Peng, L. (2012). Cell type-specific gene expression and editing responses to chronic fluoxetine treatment in the in vivo mouse brain and their relevance for stress-induced anhedonia. Neurochem. Res. 37: 2480–2495, https://doi.org/10.1007/s11064-012-0814-1.Search in Google Scholar
Li, B., Zhang, S., Zhang, H., Hertz, L., and Peng, L. (2011). Fluoxetine affects GluK2 editing, glutamate-evoked Ca(2+) influx and extracellular signal-regulated kinase phosphorylation in mouse astrocytes. J. Psychiatry Neurosci. 36: 322–338, https://doi.org/10.1503/jpn.100094.Search in Google Scholar
Li, Y.-J., Duan, G.-F., Sun, J.-H., Wu, D., Ye, C., Zang, Y.-Y., Chen, G.-Q., Shi, Y.-Y., Wang, J., Zhang, W., et al.. (2019). Neto proteins regulate gating of the kainate-type glutamate receptor GluK2 through two binding sites. J. Biol. Chem. 294: 17889–17902, https://doi.org/10.1074/jbc.ra119.008631.Search in Google Scholar
Licht, K., Kapoor, U., Amman, F., Picardi, E., Martin, D., Bajad, P., and Jantsch, M.F. (2019). A high resolution A-to-I editing map in the mouse identifies editing events controlled by pre-mRNA splicing. Genome Res. 29: 1453–1463, https://doi.org/10.1101/gr.242636.118.Search in Google Scholar
Licht, K., Kapoor, U., Mayrhofer, E., and Jantsch, M.F. (2016). Adenosine to Inosine editing frequency controlled by splicing efficiency. Nucleic Acids Res. 44: 6398–6408, https://doi.org/10.1093/nar/gkw325.Search in Google Scholar
Lomash, R.M., Sheng, N., Li, Y., Nicoll, R.A., and Roche, K.W. (2017). Phosphorylation of the kainate receptor (KAR) auxiliary subunit Neto2 at serine 409 regulates synaptic targeting of the KAR subunit GluK1. J. Biol. Chem. 292: 15369–15377, https://doi.org/10.1074/jbc.m117.787903.Search in Google Scholar
Lomeli, H., Wisden, W., Köhler, M., Keinänen, K., Sommer, B., and Seeburg, P.H. (1992). High-affinity kainate a domoate receptors in rat brain. FEBS (Fed. Eur. Biochem. Soc.) Lett. 307: 139–143, https://doi.org/10.1016/0014-5793(92)80753-4.Search in Google Scholar
Lopez, M.N., Wilding, T.J., and Huettner, J.E. (2013). Q/R site interactions with the M3 helix in GluK2 kainate receptor channels revealed by thermodynamic mutant cycles. J. Gen. Physiol. 142: 225–239, https://doi.org/10.1085/jgp.201311000.Search in Google Scholar PubMed PubMed Central
Lowe, D.L., Jahn, K., and Smith, D.O. (1997). Glutamate receptor editing in the mammalian hippocampus and avian neurons. Mol. Brain Res. 48: 37–44, https://doi.org/10.1016/s0169-328x(97)00072-7.Search in Google Scholar
Lv, Q., Liu, Y., Han, D., Xu, J., Zong, Y.-Y., Wang, Y., and Zhang, G.-Y. (2012). Neuroprotection of GluK1 kainate receptor agonist ATPA against ischemic neuronal injury through inhibiting GluK2 kainate receptor-JNK3 pathway via GABA(A) receptors. Brain Res. 1456: 1–13, https://doi.org/10.1016/j.brainres.2012.03.050.Search in Google Scholar
Lyddon, R., Navarrett, S., and Dracheva, S. (2012). Ionotropic glutamate receptor mRNA editing in the prefrontal cortex: no alterations in schizophrenia or bipolar disorder. J. Psychiatry Neurosci. 37: 267–272, https://doi.org/10.1503/jpn.110107.Search in Google Scholar
Ma-Högemeier, Z.-L., Körber, C., Werner, M., Racine, D., Muth-Köhne, E., Tapken, D., and Hollmann, M. (2010). Oligomerization in the endoplasmic reticulum and intracellular trafficking of kainate receptors are subunit-dependent but not editing-dependent. J. Neurochem. 113: 1403–1415.10.1111/j.1471-4159.2009.06559.xSearch in Google Scholar
Maingret, F., Lauri, S.E., Taira, T., and Isaac, J.T.R. (2005). Profound regulation of neonatal CA1 rat hippocampal GABAergic transmission by functionally distinct kainate receptor populations. J. Physiol. 567: 131–142, https://doi.org/10.1113/jphysiol.2005.089474.Search in Google Scholar
Maiorov, S.A., Zinchenko, V.P., Gaidin, S.G., and Kosenkov, A.M. (2021). Potential mechanism of GABA secretion in response to the activation of GluK1-containing kainate receptors. Neurosci. Res. 171: 27–33, https://doi.org/10.1016/j.neures.2021.03.009.Search in Google Scholar
Mathew, S.S., Pozzo-Miller, L., and Hablitz, J.J. (2008). Kainate modulates presynaptic GABA release from two vesicle pools. J. Neurosci. 28: 725–731, https://doi.org/10.1523/jneurosci.3625-07.2008.Search in Google Scholar
Melyan, Z., Lancaster, B., and Wheal, H.V. (2004). Metabotropic regulation of intrinsic excitability by synaptic activation of kainate receptors. J. Neurosci. 24: 4530–4534, https://doi.org/10.1523/jneurosci.5356-03.2004.Search in Google Scholar
Michishita, M., Ikeda, T., Nakashiba, T., Ogawa, M., Tashiro, K., Honjo, T., Doi, K., Itohara, S., and Endo, S. (2003). A novel gene, Btcl1, encoding CUB and LDLa domains is expressed in restricted areas of mouse brain. Biochem. Biophys. Res. Commun. 306: 680–686, https://doi.org/10.1016/s0006-291x(03)01035-0.Search in Google Scholar
Molnár, E. (2013). Are Neto1 and APP auxiliary subunits of NMDA receptors? J. Neurochem. 126: 551–553.10.1111/jnc.12339Search in Google Scholar PubMed
Mott, D.D., Benveniste, M., and Dingledine, R.J. (2008). pH-dependent inhibition of kainate receptors by zinc. J. Neurosci. 28: 1659–1671, https://doi.org/10.1523/jneurosci.3567-07.2008.Search in Google Scholar
Mott, D.D., Washburn, M.S., Zhang, S., and Dingledine, R.J. (2003). Subunit-dependent modulation of kainate receptors by extracellular protons and polyamines. J. Neurosci. 23: 1179–1188, https://doi.org/10.1523/jneurosci.23-04-01179.2003.Search in Google Scholar
Mulle, C., Sailer, A., Swanson, G.T., Brana, C., O’Gorman, S., Bettler, B., and Heinemann, S.F. (2000). Subunit composition of kainate receptors in hippocampal interneurons. Neuron 28: 475–484, https://doi.org/10.1016/s0896-6273(00)00126-4.Search in Google Scholar
Negrete-Díaz, J.V., Sihra, T.S., Flores, G., and Rodríguez-Moreno, A. (2018). Non-canonical mechanisms of presynaptic kainate receptors controlling glutamate release. Front. Mol. Neurosci. 11: 128.10.3389/fnmol.2018.00128Search in Google Scholar PubMed PubMed Central
Ng, D., Pitcher, G.M., Szilard, R.K., Sertié, A., Kanisek, M., Clapcote, S.J., Lipina, T., Kalia, L.V., Joo, D., McKerlie, C., et al.. (2009). Neto1 is a novel CUB-domain NMDA receptor-interacting protein required for synaptic plasticity and learning. PLoS Biol. 7: e41, https://doi.org/10.1371/journal.pbio.1000041.Search in Google Scholar PubMed PubMed Central
Nishikura, K. (2010). Functions and regulation of RNA editing by ADAR deaminases. Annu. Rev. Biochem. 79: 321–349, https://doi.org/10.1146/annurev-biochem-060208-105251.Search in Google Scholar PubMed PubMed Central
Nishikura, K. (2016). A-to-I editing of coding and non-coding RNAs by ADARs. Nat. Rev. Mol. Cell Biol. 17: 83–96, https://doi.org/10.1038/nrm.2015.4.Search in Google Scholar PubMed PubMed Central
Nutt, S.L., Hoo, K.H., Rampersad, V., Deverill, R.M., Elliott, C.E., Fletcher, E.J., Adams, S.L., Korczak, B., Foldes, R.L., and Kamboj, R.K. (1994). Molecular characterization of the human EAA5 (GluR7) receptor: a high-affinity kainate receptor with novel potential RNA editing sites. Recept. Channel 2: 315–326.Search in Google Scholar
Olsen, D.P., Dunlap, K., and Jacob, M.H. (2007). Kainate receptors and RNA editing in cholinergic neurons. J. Neurochem. 101: 327–341, https://doi.org/10.1111/j.1471-4159.2006.04359.x.Search in Google Scholar PubMed
Orav, E., Atanasova, T., Shintyapina, A., Kesaf, S., Kokko, M., Partanen, J., Taira, T., and Lauri, S.E. (2017). NETO1 guides development of glutamatergic connectivity in the Hippocampus by regulating axonal kainate receptors. eNeuro 4, https://doi.org/10.1523/ENEURO.0048-17.2017.Search in Google Scholar PubMed PubMed Central
Orth, A., Tapken, D., and Hollmann, M. (2013). The delta subfamily of glutamate receptors: characterization of receptor chimeras and mutants. Eur. J. Neurosci. 37: 1620–1630, https://doi.org/10.1111/ejn.12193.Search in Google Scholar PubMed
Palacios-Filardo, J., Aller, M.I., and Lerma, J. (2016). Synaptic targeting of kainate receptors. Cerebr. Cortex 26: 1464–1472, https://doi.org/10.1093/cercor/bhu244.Search in Google Scholar
Panchenko, V.A., Glasser, C.R., and Mayer, M.L. (2001). Structural similarities between glutamate receptor channels and K(+) channels examined by scanning mutagenesis. J. Gen. Physiol. 117: 345–360, https://doi.org/10.1085/jgp.117.4.345.Search in Google Scholar
Paramo, T., Brown, P.M.G.E., Musgaard, M., Bowie, D., and Biggin, P.C. (2017). Functional validation of heteromeric kainate receptor models. Biophys. J. 113: 2173–2177, https://doi.org/10.1016/j.bpj.2017.08.047.Search in Google Scholar
Paschen, W. and Djuricic, B. (1994). Extent of RNA editing of glutamate receptor subunit GluR5 in different brain regions of the rat. Cell. Mol. Neurobiol. 14: 259–270, https://doi.org/10.1007/bf02088324.Search in Google Scholar
Paschen, W. and Djuricic, B. (1995). Regional differences in the extent of RNA editing of the glutamate receptor subunits GluR2 and GluR6 in rat brain. J. Neurosci. Methods 56: 21–29, https://doi.org/10.1016/0165-0270(94)00085-u.Search in Google Scholar
Paschen, W., Dux, E., and Djuricic, B. (1994a). Developmental changes in the extent of RNA editing of glutamate receptor subunit GluR5 in rat brain. Neurosci. Lett. 174: 109–112, https://doi.org/10.1016/0304-3940(94)90131-7.Search in Google Scholar
Paschen, W., Hedreen, J.C., and Ross, C.A. (1994b). RNA editing of the glutamate receptor subunits GluR2 and GluR6 in human brain tissue. J. Neurochem. 63: 1596–1602, https://doi.org/10.1046/j.1471-4159.1994.63051596.x.Search in Google Scholar
Paschen, W., Schmitt, J., Dux, E., and Djuricic, B. (1995). Temporal analysis of the upregulation of GluR5 mRNA editing with age: regional evaluation. Brain Res. Dev. Brain Res. 86: 359–363, https://doi.org/10.1016/0165-3806(95)00042-c.Search in Google Scholar
Paschen, W., Schmitt, J., Gissel, C., and Dux, E. (1997). Developmental changes of RNA editing of glutamate receptor subunits GluR5 and GluR6: in vivo versus in vitro. Brain Res. Dev. Brain Res. 98: 271–280, https://doi.org/10.1016/s0165-3806(96)00193-9.Search in Google Scholar
Paschen, W., Schmitt, J., and Uto, A. (1996). RNA editing of glutamate receptor subunits GluR2, GluR5 and GluR6 in transient cerebral ischemia in the rat. J. Cerebr. Blood Flow Metabol. 16: 548–556, https://doi.org/10.1097/00004647-199607000-00004.Search in Google Scholar PubMed
Paternain, A.V., Herrera, M.T., Nieto, M.A., and Lerma, J. (2000). GluR5 and GluR6 kainate receptor subunits coexist in hippocampal neurons and coassemble to form functional receptors. J. Neurosci. 20: 196–205, https://doi.org/10.1523/jneurosci.20-01-00196.2000.Search in Google Scholar
Paul, M.S. and Bass, B.L. (1998). Inosine exists in mRNA at tissue-specific levels and is most abundant in brain mRNA. EMBO J. 17: 1120–1127, https://doi.org/10.1093/emboj/17.4.1120.Search in Google Scholar
Perrais, D., Pinheiro, P.S., Jane, D.E., and Mulle, C. (2009). Antagonism of recombinant and native GluK3-containing kainate receptors. Neuropharmacology 56: 131–140, https://doi.org/10.1016/j.neuropharm.2008.08.002.Search in Google Scholar
Petrovic, M.M., Viana da Silva, S., Clement, J.P., Vyklicky, L., Mulle, C., González-González, I.M., and Henley, J.M. (2017). Metabotropic action of postsynaptic kainate receptors triggers hippocampal long-term potentiation. Nat. Neurosci. 20: 529–539, https://doi.org/10.1038/nn.4505.Search in Google Scholar
Pinheiro, P.S., Lanore, F., Veran, J., Artinian, J., Blanchet, C., Crépel, V., Perrais, D., and Mulle, C. (2013). Selective block of postsynaptic kainate receptors reveals their function at hippocampal mossy fiber synapses. Cerebr. Cortex 23: 323–331, https://doi.org/10.1093/cercor/bhs022.Search in Google Scholar
Pinheiro, P.S., Perrais, D., Coussen, F., Barhanin, J., Bettler, B., Mann, J.R., Malva, J.O., Heinemann, S.F., and Mulle, C. (2007). GluR7 is an essential subunit of presynaptic kainate autoreceptors at hippocampal mossy fiber synapses. Proc. Natl. Acad. Sci. U. S. A. 104: 12181–12186, https://doi.org/10.1073/pnas.0608891104.Search in Google Scholar
Pinto, Y., Cohen, H.Y., and Levanon, E.Y. (2014). Mammalian conserved ADAR targets comprise only a small fragment of the human editosome. Genome Biol. 15: R5, https://doi.org/10.1186/gb-2014-15-1-r5.Search in Google Scholar
Rodrigues, R.J. and Lerma, J. (2012). Metabotropic signaling by kainate receptors. WIREs Membr. Transp. Signal 1: 399–410, https://doi.org/10.1002/wmts.35.Search in Google Scholar
Rodríguez-Moreno, A. and Lerma, J. (1998). Kainate receptor modulation of GABA release involves a metabotropic function. Neuron 20: 1211–1218.10.1016/S0896-6273(00)80501-2Search in Google Scholar
Rodríguez-Moreno, A., López-García, J.C., and Lerma, J. (2000). Two populations of kainate receptors with separate signaling mechanisms in hippocampal interneurons. Proc. Natl. Acad. Sci. U. S. A. 97: 1293–1298.10.1073/pnas.97.3.1293Search in Google Scholar PubMed PubMed Central
Ruiz, A., Sachidhanandam, S., Utvik, J.K., Coussen, F., and Mulle, C. (2005). Distinct subunits in heteromeric kainate receptors mediate ionotropic and metabotropic function at hippocampal mossy fiber synapses. J. Neurosci. 25: 11710–11718, https://doi.org/10.1523/jneurosci.4041-05.2005.Search in Google Scholar
Sailer, A., Swanson, G.T., Pérez-Otaño, I., O’Leary, L., Malkmus, S.A., Dyck, R.H., Dickinson-Anson, H., Schiffer, H.H., Maron, C., Yaksh, T.L., et al.. (1999). Generation and analysis of GluR5(Q636R) kainate receptor mutant mice. J. Neurosci. 19: 8757–8764, https://doi.org/10.1523/JNEUROSCI.19-20-08757.1999.Search in Google Scholar
Sakha, P., Vesikansa, A., Orav, E., Heikkinen, J., Kukko-Lukjanov, T.-K., Shintyapina, A., Franssila, S., Jokinen, V., Huttunen, H.J., and Lauri, S.E. (2016). Axonal kainate receptors modulate the strength of efferent connectivity by regulating presynaptic differentiation. Front. Cell. Neurosci. 10: 3, https://doi.org/10.3389/fncel.2016.00003.Search in Google Scholar
Sakurai, M., Ueda, H., Yano, T., Okada, S., Terajima, H., Mitsuyama, T., Toyoda, A., Fujiyama, A., Kawabata, H., and Suzuki, T. (2014). A biochemical landscape of A-to-I RNA editing in the human brain transcriptome. Genome Res. 24: 522–534, https://doi.org/10.1101/gr.162537.113.Search in Google Scholar
Schiffer, H.H., Swanson, G.T., Masliah, E., and Heinemann, S.F. (2000). Unequal expression of allelic kainate receptor GluR7 mRNAs in human brains. J. Neurosci. 20: 9025–9033, https://doi.org/10.1523/jneurosci.20-24-09025.2000.Search in Google Scholar
Schmitt, J., Dux, E., Gissel, C., and Paschen, W. (1996). Regional analysis of developmental changes in the extent of GluR6 mRNA editing in rat brain. Brain Res Dev Brain Res 91: 153–157, https://doi.org/10.1016/0165-3806(95)00175-1.Search in Google Scholar
Scott, R., Lalic, T., Kullmann, D.M., Capogna, M., and Rusakov, D.A. (2008). Target-cell specificity of kainate autoreceptor and Ca2+-store-dependent short-term plasticity at hippocampal mossy fiber synapses. J. Neurosci. 28: 13139–13149, https://doi.org/10.1523/jneurosci.2932-08.2008.Search in Google Scholar PubMed PubMed Central
Segerstråle, M., Juuri, J., Lanore, F., Piepponen, P., Lauri, S.E., Mulle, C., and Taira, T. (2010). High firing rate of neonatal hippocampal interneurons is caused by attenuation of afterhyperpolarizing potassium currents by tonically active kainate receptors. J. Neurosci. 30: 6507–6514, https://doi.org/10.1523/JNEUROSCI.4856-09.2010.Search in Google Scholar PubMed PubMed Central
Semyanov, A. and Kullmann, D.M. (2001). Kainate receptor-dependent axonal depolarization and action potential initiation in interneurons. Nat. Neurosci. 4: 718–723, https://doi.org/10.1038/89506.Search in Google Scholar PubMed
Sheng, N., Shi, Y.S., Lomash, R.M., Roche, K.W., and Nicoll, R.A. (2015). Neto auxiliary proteins control both the trafficking and biophysical properties of the kainate receptor GluK1. Elife 4, https://doi.org/10.7554/eLife.11682.Search in Google Scholar PubMed PubMed Central
Sheng, N., Shi, Y.S., and Nicoll, R.A. (2017). Amino-terminal domains of kainate receptors determine the differential dependence on Neto auxiliary subunits for trafficking. Proc. Natl. Acad. Sci. U. S. A. 114: 1159–1164, https://doi.org/10.1073/pnas.1619253114.Search in Google Scholar
Shin, R.-M., Tully, K., Li, Y., Cho, J.-H., Higuchi, M., Suhara, T., and Bolshakov, V.Y. (2010). Hierarchical order of coexisting pre- and postsynaptic forms of long-term potentiation at synapses in amygdala. Proc. Natl. Acad. Sci. U. S. A. 107: 19073–19078, https://doi.org/10.1073/pnas.1009803107.Search in Google Scholar
Silberberg, G., Lundin, D., Navon, R., and Öhman, M. (2012). Deregulation of the A-to-I RNA editing mechanism in psychiatric disorders. Hum. Mol. Genet. 21: 311–321, https://doi.org/10.1093/hmg/ddr461.Search in Google Scholar
Sommer, B., Burnashev, N., Verdoorn, T.A., Keinänen, K., Sakmann, B., and Seeburg, P.H. (1992). A glutamate receptor channel with high affinity for domoate and kainate. EMBO J. 11: 1651–1656, https://doi.org/10.1002/j.1460-2075.1992.tb05211.x.Search in Google Scholar
Sommer, B., Köhler, M., Sprengel, R., and Seeburg, P.H. (1991). RNA editing in brain controls a determinant of ion flow in glutamate-gated channels. Cell 67: 11–19, https://doi.org/10.1016/0092-8674(91)90568-j.Search in Google Scholar
Stöhr, H., Berger, C., Fröhlich, S., and Weber, B.H.F. (2002). A novel gene encoding a putative transmembrane protein with two extracellular CUB domains and a low-density lipoprotein class A module: isolation of alternatively spliced isoforms in retina and brain. Gene 286: 223–231.10.1016/S0378-1119(02)00438-9Search in Google Scholar
Straub, C., Hunt, D.L., Yamasaki, M., Kim, K.S., Watanabe, M., Castillo, P.E., and Tomita, S. (2011a). Distinct functions of kainate receptors in the brain are determined by the auxiliary subunit Neto1. Nat. Neurosci. 14: 866–873, https://doi.org/10.1038/nn.2837.Search in Google Scholar PubMed PubMed Central
Straub, C., Zhang, W., and Howe, J.R. (2011b). Neto2 modulation of kainate receptors with different subunit compositions. J. Neurosci. 31: 8078–8082, https://doi.org/10.1523/jneurosci.0024-11.2011.Search in Google Scholar
Strutz-Seebohm, N., Seebohm, G., Shumilina, E., Mack, A.F., Wagner, H.-J., Lampert, A., Grahammer, F., Henke, G., Just, L., Skutella, T., et al.. (2005). Glucocorticoid adrenal steroids and glucocorticoid-inducible kinase isoforms in the regulation of GluR6 expression. J. Physiol. 565: 391–401, https://doi.org/10.1113/jphysiol.2004.079624.Search in Google Scholar PubMed PubMed Central
Sun, H.Y., Bartley, A.F., and Dobrunz, L.E. (2009). Calcium-permeable presynaptic kainate receptors involved in excitatory short-term facilitation onto somatostatin interneurons during natural stimulus patterns. J. Neurophysiol. 101: 1043–1055, https://doi.org/10.1152/jn.90286.2008.Search in Google Scholar PubMed PubMed Central
Swanson, G.T., Feldmeyer, D., Kaneda, M., and Cull-Candy, S.G. (1996). Effect of RNA editing and subunit co-assembly single-channel properties of recombinant kainate receptors. J. Physiol. (Camb.) 492: 129–142, https://doi.org/10.1113/jphysiol.1996.sp021295.Search in Google Scholar
Tang, M., Ivakine, E., Mahadevan, V., Salter, M.W., and McInnes, R.R. (2012). Neto2 interacts with the scaffolding protein GRIP and regulates synaptic abundance of kainate receptors. PLoS One 7: e51433, https://doi.org/10.1371/journal.pone.0051433.Search in Google Scholar
Tang, M., Pelkey, K.A., Ng, D., Ivakine, E., McBain, C.J., Salter, M.W., and McInnes, R.R. (2011). Neto1 is an auxiliary subunit of native synaptic kainate receptors. J. Neurosci. 31: 10009–10018, https://doi.org/10.1523/jneurosci.6617-10.2011.Search in Google Scholar
Thomas, J.M. and Beal, P.A. (2017). How do ADARs bind RNA? New protein-RNA structures illuminate substrate recognition by the RNA editing ADARs. Bioessays 39, https://doi.org/10.1002/bies.201600187.Search in Google Scholar
Vargas, J.R., Takahashi, D.K., Thomson, K.E., and Wilcox, K.S. (2013). The expression of kainate receptor subunits in hippocampal astrocytes after experimentally induced status epilepticus. J. Neuropathol. Exp. Neurol. 72: 919–932, https://doi.org/10.1097/nen.0b013e3182a4b266.Search in Google Scholar
Veran, J., Kumar, J., Pinheiro, P.S., Athané, A., Mayer, M.L., Perrais, D., and Mulle, C. (2012). Zinc potentiates GluK3 glutamate receptor function by stabilizing the ligand binding domain dimer interface. Neuron 76: 565–578, https://doi.org/10.1016/j.neuron.2012.08.027.Search in Google Scholar
Vignes, M., Clarke, V.R.J., Parry, M.J., Bleakman, D., Lodge, D., Ornstein, P.L., and Collingridge, G.L. (1998). The GluR5 subtype of kainate receptor regulates excitatory synaptic transmission in areas CA1 and CA3 of the rat hippocampus. Neuropharmacology 37: 1269–1277, https://doi.org/10.1016/s0028-3908(98)00148-8.Search in Google Scholar
Vissel, B., Royle, G.A., Christie, B.R., Schiffer, H.H., Ghetti, A., Tritto, T., Perez-Otano, I., Radcliffe, R.A., Seamans, J., Sejnowski, T., et al.. (2001). The role of RNA editing of kainate receptors in synaptic plasticity and seizures. Neuron 29: 217–227, https://doi.org/10.1016/s0896-6273(01)00192-1.Search in Google Scholar
Wahlstedt, H., Daniel, C., Ensterö, M., and Ohman, M. (2009). Large-scale mRNA sequencing determines global regulation of RNA editing during brain development. Genome Res. 19: 978–986, https://doi.org/10.1101/gr.089409.108.Search in Google Scholar PubMed PubMed Central
Wang, L.Y., Dudek, E.M., Browning, M.D., and MacDonald, J.F. (1994). Modulation of AMPA/kainate receptors in cultured murine hippocampal neurones by protein kinase C. J. Physiol. 475: 431–437, https://doi.org/10.1113/jphysiol.1994.sp020083.Search in Google Scholar PubMed PubMed Central
Wang, L.Y., Salter, M.W., and MacDonald, J.F. (1991). Regulation of kainate receptors by cAMP-dependent protein kinase and phosphatases. Science 253: 1132–1135, https://doi.org/10.1126/science.1653455.Search in Google Scholar PubMed
Werner, P., Voigt, M., Keinänen, K., Wisden, W., and Seeburg, P.H. (1991). Cloning of a putative high-affinity kainate receptor expressed predominantly in hippocampal CA3 cells. Nature 351: 742–744, https://doi.org/10.1038/351742a0.Search in Google Scholar PubMed
Wilding, T.J., Chai, Y.H., and Huettner, J.E. (1998). Inhibition of rat neuronal kainate receptors by cis-unsaturated fatty acids. J. Physiol. 513: 331–339, https://doi.org/10.1111/j.1469-7793.1998.331bb.x.Search in Google Scholar PubMed PubMed Central
Wilding, T.J., Chen, K., and Huettner, J.E. (2010). Fatty acid modulation and polyamine block of GluK2 kainate receptors analyzed by scanning mutagenesis. J. Gen. Physiol. 136: 339–352, https://doi.org/10.1085/jgp.201010442.Search in Google Scholar PubMed PubMed Central
Wilding, T.J., Fulling, E., Zhou, Y., and Huettner, J.E. (2008). Amino acid substitutions in the pore helix of GluR6 control inhibition by membrane fatty acids. J. Gen. Physiol. 132: 85–99, https://doi.org/10.1085/jgp.200810009.Search in Google Scholar PubMed PubMed Central
Wilding, T.J. and Huettner, J.E. (2019). Cadmium opens GluK2 kainate receptors with cysteine substitutions at the M3 helix bundle crossing. J. Gen. Physiol. 151: 435–451, https://doi.org/10.1085/jgp.201812234.Search in Google Scholar PubMed PubMed Central
Wilding, T.J., Zhou, Y., and Huettner, J.E. (2005). Q/R site editing controls kainate receptor inhibition by membrane fatty acids. J. Neurosci. 25: 9470–9478, https://doi.org/10.1523/jneurosci.2826-05.2005.Search in Google Scholar
Wright, A. and Vissel, B. (2012). The essential role of AMPA receptor GluR2 subunit RNA editing in the normal and diseased brain. Front. Mol. Neurosci. 5: 34, https://doi.org/10.3389/fnmol.2012.00034.Search in Google Scholar PubMed PubMed Central
Xu, X., Sun, R., and Jin, R. (2008). The effect of the ketogenic diet on hippocampal GluR5 and Glu(6 mRNA expression and Q/R site editing in the kainate-induced epilepsy model. Epilepsy Behav. 13: 445–448, https://doi.org/10.1016/j.yebeh.2008.05.020.Search in Google Scholar PubMed
Zhang, W., St-Gelais, F., Grabner, C.P., Trinidad, J.C., Sumioka, A., Morimoto-Tomita, M., Kim, K.S., Straub, C., Burlingame, A.L., Howe, J.R., et al.. (2009). A transmembrane accessory subunit that modulates kainate-type glutamate receptors. Neuron 61: 385–396, https://doi.org/10.1016/j.neuron.2008.12.014.Search in Google Scholar PubMed PubMed Central
Zhu, Q.-J., Kong, F.-S., Xu, H., Wang, Y., Du, C.-P., Sun, C.-C., Liu, Y., Li, T., and Hou, X.-Y. (2014). Tyrosine phosphorylation of GluK2 up-regulates kainate receptor-mediated responses and downstream signaling after brain ischemia. Proc. Natl. Acad. Sci. U.S.A. 111: 13990–13995, https://doi.org/10.1073/pnas.1403493111.Search in Google Scholar PubMed PubMed Central
Zinchenko, V.P., Gaidin, S.G., Teplov, I.Y., and Kosenkov, A.M. (2017). Inhibition of spontaneous synchronous activity of hippocampal neurons by excitation of GABAergic neurons. Biochem. Moscow Suppl. Ser. A. 11: 261–274, https://doi.org/10.1134/s1990747817040110.Search in Google Scholar
Zinchenko, V.P., Kosenkov, A.M., Gaidin, S.G., Sergeev, A.I., Dolgacheva, L.P., and Tuleukhanov, S.T. (2021). Properties of GABAergic neurons containing calcium-permeable kainate and AMPA-receptors. Life 11, https://doi.org/10.3390/life11121309.Search in Google Scholar PubMed PubMed Central
© 2022 Walter de Gruyter GmbH, Berlin/Boston
