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.
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