ReviewPotassium fluxes across the endoplasmic reticulum and their role in endoplasmic reticulum calcium homeostasis
Graphical abstract
Introduction
There are a number of known and suspected channels and exchangers in the endoplasmic reticulum (ER) membrane that may mediate potassium flux through the ER membrane. They include the potassium permeable trimeric intracellular cation channels (TRIC channels), ATP-sensitive and Ca2+-activated potassium channels (KATP and KCa channels, respectively), most abundant in the plasma membrane but found also in the mitochondrial inner membrane, the mitochondrial potassium-hydrogen exchanger (KHE) and, potentially, the ryanodine receptor (RYR) and inositol 1,4,5-trisphosphate receptor (IP3R) ER Ca2+ release channels both permeable for potassium. Apart from the TRIC channels, which are found only in the ER, the functionality of potassium channels in the ER has remained unclear. These channels are assembled in the ER and then transported to the Golgi apparatus and from the Golgi apparatus to their final destination on the cell surface or elsewhere. It is therefore difficult to establish whether these channels play a functional role in the ER membrane. Nevertheless, there is evidence that some of these channel isoforms/subunits tend to be expressed relatively robustly in the ER compared with other cell structures. The role that potassium fluxes play across the ER membrane has also remained elusive. It has been proposed that their main role is to balance the charge movement that occurs during Ca2+ release and uptake from or to ER. Here, we summarize current knowledge on ER potassium channels and fluxes and their potential role in ER Ca2+ uptake and release.
Section snippets
Ca2+ movement across the ER membrane requires counter-ion flux
The ER (or sarcoplasmic reticulum, SR, in muscle cells) serves as a dynamic Ca2+ store involved in several cell types in fast signaling associated with cell stimulation. As an example, in cardiomyocytes, immediately following depolarization-induced entry of extracellular Ca2+, Ca2+ release from the SR to the cytoplasm initiates cardiomyocyte contraction. Reuptake of this Ca2+ into the intra-reticular space then leads to relaxation of the cell. In neurons, Ca2+ is released from the ER during
Trimeric intracellular cation channels
In 2007, Yazawa et al. [16] discovered trimeric intracellular cation channels (TRIC) located in the ER/SR. They identified two TRIC isoforms, TRIC-A, which is expressed predominantly in the reticulum of muscle cells, and the ubiquitously expressed TRIC-B. Further reconstitution experiments have demonstrated that both proteins form voltage-dependent cation channels, permeable to K+ and Na+ but not to divalent cations or anions. Both TRIC-A and TRIC-B function as K+-permeable channels with
ATP sensitive KATP channels
The ATP-sensitive K+ channel is an octameric complex comprised of four pore-forming Kir6.X subunits, from the inward rectifier potassium channel family, that are surrounded by four regulatory sulfonylurea receptors (SURs) [24]. ATP binds Kir6.X, thus the channel contains 4 potential binding sites that inhibit its activity [24], [25]. In mammals, there are 2 pore-forming Kir6.X subunits: Kir6.1 (also known as KCNJ8) and Kir6.2 (KCNJ11) [26], [27], [28]. The regulatory SUR subunits are encoded by
Calcium-activated potassium channels
Calcium-activated potassium channels are divided into big conductance Ca2+-sensitive K+ (BKCa), intermediate conductance Ca2+-sensitive K+ (IKCa) and small conductance calcium-sensitive K+ (SKCa) channels based on their K+ conductance (for review see [47]). BKCa channels are activated by membrane depolarization and/or elevated cytosolic Ca2+ [48], [49]. In contrast, SKCa and IKCa channels are voltage insensitive and gated only by increases in cytosolic calcium [50], [51], [52]. Both BKCa and SK
Potassium-hydrogen exchanger
LETM1 (leucine zipper-EF hand-containing transmembrane 1) is a highly conserved eukaryotic protein of the mitochondrial inner membrane that has been proposed to mediate mitochondrial K+–H+ exchange [77], [78], [79], [80], [81]. It is essential for mitochondrial volume homeostasis because the H+ gradient that drives electrophoretic K+ uptake requires electroneutral K+–H+ exchange to prevent mitochondrial K+ accumulation [82], [83] (see also [84]). Indeed, LETM1 inactivation causes severe matrix
Ryanodine and IP3 receptors
Ryanodine receptors (RYRs) are located in the ER/SR membrane and are responsible for the release of Ca2+ from the sarcoplasmic/endoplasmic reticulum in excitable cells, such as different muscle cells and neurons. In cells of striated muscle, release occurs via coupling to the dihydropyridine receptor, whereas in cardiomyocytes, the primary mechanism is calcium-induced calcium release from the sarcoplasmic reticulum. There are three different RYRs isoforms in mammals: RYR1, primarily expressed
Other roles for ER potassium channels
What other roles, if at all, do ER K+ channels play? It is unlikely that the ER, which makes up approximately one tenth of the cell's total volume and has no substantial membrane potential, could store sufficient K+ to affect basal cytosolic K+ levels significantly (∼120–150 mM). The absence of a marked ER transmembrane potential appears to indicate that K+ fluxes across the ER membrane would likely not considerably affect the K+ lumen concentration equilibrated by water flux; thus, [K+] is
Hypothesis
All of this evidence allows the following suggested mechanism of electrical charge balance across the ER/SR membrane (Fig. 2). During the Ca2+ uptake phase, SERCA extrudes two or three protons per two calcium ions pumped into the ER. The extruded protons re-enter via KHE, driving K+ ions out from the ER lumen. Potassium ions, in turn, re-enter the ER via TRIC and/or SKCa channels. Notably, the latter (ER SKCa-s) are under the control of cytoplasmic Ca2+ and may be activated by high cytoplasmic
Conflict of interest
None declared.
Acknowledgements
This work was supported by grants from the Estonian Research Council (IUT2-5) and by the European Regional Development Fund. We also thank Dr. Miriam A. Hickey for her assistance with proofreading.
References (106)
- et al.
Electron probe X-ray microanalysis of post-tetanic Ca2+ and Mg2+ movements across the sarcoplasmic reticulum in situ
J. Biol. Chem.
(1985) - et al.
Evidence for proton countertransport by the sarcoplasmic reticulum Ca2+-ATPase during calcium transport in reconstituted proteoliposomes with low ionic permeability
J. Biol. Chem.
(1990) - et al.
H+ countertransport and electrogenicity of the sarcoplasmic reticulum Ca2+ pump in reconstituted proteoliposomes
Biophys. J.
(1993) - et al.
Green fluorescent protein as a noninvasive intracellular pH indicator
Biophys. J.
(1998) - et al.
Kinetics of the (Ca2+), (H+), and (Mg2+) interaction with the ion-binding sites of the SR Ca-ATPase
Biophys. J.
(2002) - et al.
Intracellular calcium release channels mediate their own countercurrent: the ryanodine receptor case study
Biophys. J.
(2008) - et al.
Ca2+ overload and sarcoplasmic reticulum instability in tric-a null skeletal muscle
J. Biol. Chem.
(2010) - et al.
TRIC-A channels in vascular smooth muscle contribute to blood pressure maintenance
Cell Metab.
(2011) - et al.
Sarcoplasmic reticulum K(+) (TRIC) channel does not carry essential countercurrent during Ca(2+) release
Biophys. J.
(2013) - et al.
Genomic organization and expression of KCNJ8/Kir6.1: a gene encoding a subunit of an ATP-sensitive potassium channel
Gene
(1998)
Cloning and functional characterization of a novel ATP-sensitive potassium channel ubiquitously expressed in rat tissues, including pancreatic islets, pituitary, skeletal muscle, and heart
J. Biol. Chem.
A new ER trafficking signal regulates the subunit stoichiometry of plasma membrane K(ATP) channels
Neuron
Differential interaction of glimepiride and glibenclamide with the beta-cell sulfonylurea receptor. II. Photoaffinity labeling of a 65 kDa protein by [3H]glimepiride
Biochim. Biophys. Acta
Cardiac sulfonylurea receptor short form-based channels confer a glibenclamide-insensitive KATP activity
J. Mol. Cell Cardiol.
Redox regulation of the mitochondrial K(ATP) channel in cardioprotection
Biochim. Biophys. Acta
Mitochondrial ATP-sensitive K+ channels are redox-sensitive pathways that control reactive oxygen species production
Free Radic. Biol. Med.
Cloning and functional characterization of novel large conductance calcium-activated potassium channel beta-subunits, hKCNMB3 and hKCNMB4
J. Biol. Chem.
Primary sequence and immunological characterization of beta-subunit of high conductance Ca2+-activated K+ channel from smooth muscle
J. Biol. Chem.
Cloning and functional expression of two families of beta-subunits of the large conductance calcium-activated K+ channel
J. Biol. Chem.
Calmodulin mediates calcium-dependent activation of the intermediate conductance KCa channel, IKCa1
J. Biol. Chem.
Calcium-activated potassium channels
Curr. Opin. Neurobiol.
A novel MaxiK splice variant exhibits dominant-negative properties for surface expression
J. Biol. Chem.
Differential trafficking of carbocyl isoforms of Ca2+-gated (Slo1) potassium channels
FEBS Lett.
Calcium activated potassium channels in cultured astrocytes
Neuroscience
Trypanosome Letm1 protein is essential for mitochondrial potassium homeostasis
J. Biol. Chem.
The LETM1/YOL027 gene family encodes a factor of the mitochondrial K+ homeostasis with a potential role in the Wolf-Hirschhorn syndrome
J. Biol. Chem.
Chemiosmotic coupling in oxidative and photosynthetic phosphorylation. 1966
Biochim. Biophys. Acta
Novel components of an active mitochondrial K(+)/H(+) exchange
J. Biol. Chem.
Quinine inhibition of Na+ and K+ transport provides evidence for two cation/H+ exchangers in rat liver mitochondria
J. Biol. Chem.
Is ryanodine receptor a calcium or magnesium channel? Roles of K+ and Mg2+ during Ca2+ release
Cell Calcium
Mitochondrial swelling impairs the transport of organelles in cerebellar granule neurons
J. Biol. Chem.
Chloride channels of intracellular membranes
FEBS Lett.
Calcium uptake and release modulated by counter-ion conductances in the sarcoplasmic reticulum of skeletal muscle
Acta Physiol. Scand.
Monovalent ion and calcium ion fluxes in sarcoplasmic reticulum
Mol. Cell. Biochem.
Reconstitution of sarcoplasmic reticulum Ca2+-ATPase vesicles lacking ion channels and demonstration of electrogenicity of Ca2+-pump
J. Biochem.
Calcium release and sarcoplasmic reticulum membrane potential in frog skeletal muscle fibers
J. Physiol.
An appraisal of the evidence for a sarcoplasmic reticulum membrane potential and its relation to calcium release in skeletal muscle
J. Muscle Res. Cell. Motil.
Calcium release and ionic changes in the sarcoplasmic reticulum of tetanized muscle: an electron-probe study
J. Cell Biol.
The effects of valinomycin on ion movements across the sarcoplasmic reticulum in frog muscle
J. Physiol.
A role of H+ flux in active Ca2+ transport into sarcoplasmic reticulum vesicles. II. H+ ejection during Ca2+ uptake
J. Biochem.
Noninvasive measurement of the pH of the endoplasmic reticulum at rest and during calcium release
Proc. Natl. Acad. Sci. U. S. A.
Endoplasmic reticulum potassium-hydrogen exchanger and small conductance calcium-activated potassium channel activities are essential for ER calcium uptake in neurons and cardiomyocytes
J. Cell. Sci.
TRIC channels are essential for Ca2+ handling in intracellular stores
Nature
The intracellular localization and function of the ATP-Sensitive K+ channel subunit Kir6.1
J. Membr. Biol.
Essential role of the TRIC-B channel in Ca2+ handling of alveolar epithelial cells and in perinatal lung maturation
Development
TRIC channels supporting efficient Ca(2+) release from intracellular stores
Pflugers Arch.
Association and stoichometry of KATP channel subunits
Neuron
Octameric stoichiometry of the KATP channel complex
J. Gen. Physiol.
Mutations in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed in the first 6 months of life, with the phenotype determined by genotype
Diabetologia
Cloning of the beta-cell high-affinity sulfonylurea receptor: a regulator of insulin secretion
Science
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