Feature Article: Selective modulation of tonically active GABAA receptor functional subgroups by G-proteins and protein kinase C

Abstract

Ionotropic receptors of γ-aminobutyric acid (GABAARs) produce two forms of inhibitory signaling: phasic inhibition triggered by activation of synaptic GABAARs at GABAergic synapses, and tonic inhibition generated in large part through persistent activation of extrasynaptic GABAARs. It has recently been demonstrated that tonic inhibition may also involve spontaneously opening GABAARs (s-GABAARs) whose activation does not require binding of γ-aminobutyric acid (GABA). Here, we examine intracellular mechanisms modulating GABAARs’ tonic effects in rat dentate gyrus granule cells (DGCs). Cellular control of s-GABAARs-delivered tonic current appears to involve signaling inputs from G-protein-dependent and -independent molecular cascades, whereas tonic GABA-dependent current in DGCs is regulated by protein kinase C. The intracellular agents that modulate s-GABAAR-generated inhibition could thus represent a generic mechanism controlling signal integration in central neural circuits. Impact statement: Here we study intracellular mechanisms which regulate inhibitory signaling delivered through continuously (tonically) open ionotropic receptors of γ-aminobutyric acid (GABA) of dentate gyrus granule cells (DGCs). We found that, apart of classical GABA-A receptors (GABAARs) which can be activated by GABA binding, a significant part of tonic inhibitory current is delivered by newly discovered spontaneously opening GABAARs (s-GABAARs), which enter active state without binding of GABA. We have also found that conventional GABAARs and s-GABAARs are regulated by different intracellular mechanisms, which may overlap and thus induce various signaling repercussions. Our results demonstrate that s-GABAARs play a key role in the mechanism that implements DGCs functional role in the brain. On top of that, since regulatory mechanisms under study are affected in a number of pathological states, our results may have broad implications for treatment of neurological disorders.