Endogenous regulators of G protein signaling proteins regulate presynaptic inhibition at rat hippocampal synapses

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Abstract
Presynaptic inhibition mediated by G protein-coupled receptors (GPCRs) can develop and decay in a few seconds. This time course is too rapid to be accounted for by the intrinsic GTPase activity of Gα subunits alone. Here, we test the hypothesis that endogenous regulators of G protein signaling (RGS proteins) are required for rapid, brief presynaptic inhibition. Endogenous G protein α subunits were uncoupled from GPCRs by treating cultures with pertussis toxin (PTX). Adenoviral expression of mutant PTX-insensitive (PTX-i) Gαi1–3 or Gαo subunits rescued adenosine-induced presynaptic inhibition in cultured hippocampal neurons. Expression of double mutant Gαi1 or Gαo subunits that were both PTX-insensitive and unable to bind RGS proteins (PTX/RGS-i) also rescued presynaptic inhibition. Presynaptic inhibition mediated by PTX/RGS-i subunits decayed much more slowly after agonist removal than that mediated by PTX-i subunits or native G proteins. The onset of presynaptic inhibition mediated by PTX/RGS-i Gαo was also slower than that mediated by PTX-i Gαo. In contrast, the onset of presynaptic inhibition mediated by PTX/RGS-i Gαi1 was similar to that mediated by PTX-i Gαi1. These results suggest that endogenous RGS proteins regulate the time course of G protein signaling in mammalian central nervous system presynaptic terminals.