Trends in Neurosciences
OpinionFGFR1–5-HT1A Heteroreceptor Complexes: Implications for Understanding and Treating Major Depression
Section snippets
Serotonin Hypothesis of Depression
The 5-HT hypothesis of major depression (see Glossary) has been at the center of understanding the neurochemical basis of this mental disorder since the 1960s. The brainstem 5-HT neurons with large monosynaptic ascending and descending pathways to the telencephalon and diencephalon and the spinal cord, respectively, were discovered in 1964 [1]. They mainly operate via volume transmission [2]. In 1967, the 5-HT uptake mechanism was found in their plasma membrane at the soma, axon, and terminal
GPCR–GPCR Heteroreceptor Complexes
The discovery of allosteric receptor–receptor interactions (RRIs) in the early 1980s provided evidence that GPCRs operate not only as monomers but also as protomers in homoreceptor and heteroreceptor complexes, in which integration of the incoming signals takes place already at the plasma membrane level through allosteric RRIs 25, 26, 27. These integrative mechanisms give sophisticated dynamics to the structure and function of these receptor assemblies in terms of modulation of recognition,
Discovery of Hippocampal FGFR1–5-HT1A Heteroreceptor Complexes and Their Enhancement of Hippocampal Plasticity
Hippocampal heteroreceptor complexes were first observed in 2012 [24]. FGFR1–5-HT1A heteroreceptor complexes were found in the pyramidal cell layer (CA1–CA4) of the rat dorsal hippocampus and in the dorsal leaflet of the dentate gyrus, but not in the cerebral cortex, using the PLA (Figure 2) 23, 24. The allosteric RRI in hippocampal cultures involved a 5-HT1A agonist-induced FGFR1 transactivation, as seen from its increased phosphorylation [24]. Furthermore, acute and repeated combined ICV
Discovery of the FGFR1–5-HT1A Heteroreceptor Complexes in Midbrain Raphe 5-HT Nerve Cells and Their Role in Enhancement of Neuroplasticity
The hippocampal results described above were bolstered by the demonstration of these heteroreceptor complexes with synergistic allosteric RRIs enhancing FGFR1 signaling also in large numbers of midbrain raphe 5-HT neurons 21, 22. Here the 5-HT1A receptor is known to have a function as an autoreceptor 8, 9, 40, 41. The FGF2–FGFR1 system was previously shown to exist in the vast majority of raphe midbrain 5-HT nerve cells 42, 43.
The dynamic agonist regulation of the FGFR1–5-HT1A heteroreceptor
Understanding the RTK–GPCR Interface Based on the Triplet Puzzle Theory
The possibility of forming heteromers between RTK and GPCR receptors can be explained using our theory of triplet puzzle, that is, the triplet puzzle theory 47, 48. Based on a mathematical approach and the experimentally known pairs of receptors that do or do not form heteromers [33], we have deduced sets of triplet amino acid homologies that may be critically involved in RRIs. It was shown how such sets of triplets may be utilized to construct a type of code that helps determine which
On the Potential Existence of D2–FGFR1 and α2A–FGFR1 Autoreceptor Complexes at the Soma–Dendritic Level of Central Catecholamine Neurons
There is strong evidence that also central dopamine (DA) and noradrenaline (NA) neurons participate in mediating antidepressant actions 6, 7, 54, 55, 56. Many antidepressant drugs are in fact serotonin–noradrenaline reuptake inhibitors (SNRIs) and triple reuptake inhibitors for depression (SNDRIs), including blockade of DA reuptake.
The evidence given above indicates that 5-HT1A autoreceptor–FGFR1 heteroreceptor complexes of the midbrain raphe serotonin neurons participate in neuroplasticity and
Concluding Remarks
Postjunctional FGFR1–5-HT1A heteroreceptor complexes exist in the hippocampal pyramidal nerve cells. Their synergistic allosteric RRIs upon agonist coactivation may exert robust antidepressant actions. Counteraction of hippocampal atrophy may potentially develop with time.
FGFR1–5-HT1A autoreceptor heterocomplexes exist in the midbrain raphe 5-HT nerve cells. Synergistic allosteric RRIs develop within them upon agonist coactivation. This may contribute to antidepressant actions by recruiting
Acknowledgments
The authors are supported by grants from the Swedish Medical Research Council (62X-00715-50-3) to K.F., and by AFA Försäkring (130328) to K.F. and D.O.B-E. A.O.T. has not received any support for this work. D.O.B-E. belongs to Academia de Biólogos Cubanos.
Glossary
- 5-HT hypothesis of major depression
- major depression is a common psychiatric disease characterized by a persistent feeling of melancholy in which the central 5-HT neurons sending ascending projections to the telencephalon and diencephalon, especially the limbic regions may be disturbed. This is supported by the antidepressant effects produced by SSRIs, which increase 5-HT neurotransmission.
- 5-HT1A
- a major receptor subtype of the 5-HT receptor family found in prejunctional and postjunctional
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2020, Biomedicine and PharmacotherapyCitation Excerpt :Valsartan, an FDA approved drug for treating high blood pressure and heart failure, was reported to improve MF [15]. 5-hydroxytryptamine 1A (5-HT1A), a receptor of 5-HT receptor family found in prejunctional and postjunctional locations of central 5-HT neurons, plays a vital role in the regulation of dopamine in sympathetic nervous system [16]. Numerous preclinical and clinical investigations have shown that sympatho-depression can successfully reduce blood pressure, attenuate left ventricular hypertrophy (LVH), and subsequently improve survival rate in rats with hypertension and heart failure and in patients with chronic heart failure [17–19].
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2019, NeuropharmacologyCitation Excerpt :More generally, the CNS cells may use the strategy of heteromers formation to achieve different functional outcomes for a single neurotransmitter input. A prototype is represented by Serotonin (5-HT) receptors, which partecipate to multiple transactivation mechaninsms and heteroreceptor complexes, involving RTKs as well as other GPCRs, thus modulating the activity of hippocampal circuits and related outputs such as mood-regulating limbic areas, counteracting the reduction of neurotrophic factor signaling and hippocampal atrophy in major depression and regulating the antidepressant actions produced by 5-HT receptor activation (Borroto-Escuela et al., 2016, 2018a). Concerning the receptor biophysical interaction, two different modes of receptor monomers assembling into oligomers have been proposed.
Glutamate heteroreceptor complexes in the brain
2018, Pharmacological ReportsCitation Excerpt :However, the formation of heteromers between the muscarinic receptors and the heteromeric GluK subunits seem possible, which can enhance the function of this type of kainate receptor. Dysfunction or disruption of the heteroreceptor complexes may lead to brain disease [5,94,99,117,118]. As an example, understanding the D2R heteroreceptor complexes and their dysfunction in schizophrenia can lead to new strategies for its treatment and for avoiding side-effects of antipsychotics known to mainly act as D2R antagonists [5,119].