Selective modulation of tonically active GABA A receptor functional subgroups by G-proteins and protein kinase C

Abstract

Ionotropic receptors of γ-aminobutyric acid (GABA_ARs) produce two forms of inhibitory signaling: phasic inhibition triggered by activation of synaptic GABA_ARs at GABAergic synapses, and tonic inhibition generated in large part through persistent activation of extrasynaptic GABA_ARs. It has recently been demonstrated that tonic inhibition may also involve spontaneously opening GABA_ARs (s-GABA_ARs) whose activation does not require binding of γ-aminobutyric acid (GABA). Here, we examine intracellular mechanisms modulating GABA_ARs’ tonic effects in rat dentate gyrus granule cells (DGCs). Cellular control of s-GABA_ARs-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-GABA_AR-generated inhibition could thus represent a generic mechanism controlling signal integration in central neural circuits.