GPCR modulation of extrasynapitic GABAA receptors

Abstract

γ-Aminobutyric acid type A (GABAA) receptors (GABAARs), the main inhibitory neurotransmitter-gated ion channels in the central nervous system, are finely tuned by other neurotransmitters and endogenous ligands. The regulation of synaptic GABAARs (sGABAARs) by G protein-coupled receptors (GPCRs) has been well characterized and is known to occur either through the conventional activation of second-messenger signalling cascades by G proteins or directly by protein–protein coupling. In contrast, research on the modulation of extrasynaptic GABAAR (eGABAARs) is still in its infancy and it remains to be determined whether both of the above mechanisms are capable of controlling eGABAAR function. In this chapter, we summarize the available literature on eGABAAR modulation by GPCRs, including GABAB, serotonin (5-HT), dopamine (DA), noradrenaline (NA) and metabotropic glutamate (mGlu) receptors. Although at present these GPCRs-eGABAARs cross-talks have been investigated in a limited number of brain areas (i.e., thalamus, cerebellum, hippocampus, striatum), it is already evident that eGABAARs show a nucleus- and neuronal type-selective regulation by GPCRs that differs from that of sGABAARs. This distinct regulation of eGABAARs versus sGABAARs by GPCRs provides mechanisms for receptor adaptation in response to a variety of physiological stimuli and under different pathophysiological conditions. Further research will advance our understanding of eGABAAR and GPCR signalling and offer novel targets for the treatment of many neurological and neuropsychiatric disorders where abnormalities in eGABAAR have been suggested to exist.