Abstract
GABAA receptors are pentameric ion channels that mediate most synaptic and tonic extrasynaptic inhibitory transmissions in the central nervous system. There are multiple GABAA receptor subtypes constructed from 19 different subunits in mammals that exhibit different regional and subcellular distributions and distinct pharmacological properties. Dysfunctional alterations of GABAA receptors are associated with various neuropsychiatric disorders. Short- and long-term plastic changes in GABAA receptors can be induced by the activation of different intracellular signaling pathways that are triggered, under physiological and pathological conditions, by calcium entering through voltage-gated calcium channels. This review discusses several mechanisms of regulation of GABAA receptor function that result from the activation of L-type voltage gated calcium channels. Calcium influx via these channels activates different signaling cascades that lead to changes in GABAA receptor transcription, phosphorylation, trafficking, and synaptic clustering, thus regulating the inhibitory synaptic strength. These plastic mechanisms regulate the interplay of synaptic excitation and inhibition that is crucial for the normal function of neuronal circuits.
Highlights
The activation of GABAA receptors in the mammalian brain is responsible for most fast synaptic inhibition
Saliba et al [64] showed that a chronic blockade of L-type voltage-gated calcium channels (VGCCs) in rat hippocampal neurons decreases the number of GABAA receptors at the synapses, in parallel with a reduction in the amplitude of miniature inhibitory postsynaptic currents (mIPSCs)
The insertion of GABAA receptors into the cell surface is regulated by a phosphorylation mechanism that involves the activation of L-type VGCCs. It was demonstrated in rat hippocampal cultures that neuronal activity leads to the accumulation of GABAA receptors composed of α5/β3 subunits at the plasma membrane, leading to the stimulation of tonic currents, without influencing receptor endocytosis. This process is mediated by calcium influx through L-type VGCCs, which induces an increase in β3 S383 phosphorylation by CaMKII [90]
Summary
The activation of GABAA receptors in the mammalian brain is responsible for most fast synaptic inhibition. This review discusses different signaling pathways activated by the calcium influx through L-type VGCCs that control GABAA receptor function by means of the regulation of receptor Membranes 2021, 11, x transcription, phosphorylation, intracellular trafficking, and syna poft1i6c clustering. These plastic mechanisms are crucial for the regulation of the interplay of synaptic excitation and inhibition that controls the function of neuronal circuits in the healthy brain (Figure 1). The basal levels of free cytoplasmic calcium in neurons are actively maintained low Membranes 2021, 11, 486
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
