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¹ Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel

G protein-activated K⁺ channels (GIRK) mediate postsynaptic inhibitory effects of neurotransmitters in the atrium and in the brain by coupling to G protein-coupled receptors (GPCRs). In neurotransmitter-dependent GIRK signalling, G is released from the heterotrimeric G complex upon GPCR activation, activating the channel and attenuating its rectification. Now it becomes clear that G is more than a mere G donor. We have proposed that G_i3–GDP regulates GIRK gating, keeping its basal activity low but priming (predisposing) the channel for activation by agonist in intact cells, and by G in excised patches. Here we have further investigated GIRK priming by G_i3 using a model in which the channel was activated by coexpression of G, and the currents were measured in intact Xenopus oocytes using the two-electrode voltage clamp technique. This method enables the bypass of GPCR activation during examination of the regulation of the channel in intact cells. Using this method, we further characterize the priming phenomenon. We tested and excluded the possibility that our estimates of priming are affected by artifacts caused by series resistance or large K⁺ fluxes. We demonstrate that both G_i3 and membrane-attached G scavenger protein, m-phosducin, reduce the basal channel activity. However, G_i3 allows robust channel activation by coexpressed G, in sharp contrast to m-phosducin, which causes a substantial reduction in the total G-induced current. Furthermore, G_i3 also does not impair the G-dependent attenuation of the channel rectification, in contrast to m-phosducin, which prevents this G-induced modulation. The G_i3-induced enhancement of direct activation of GIRK by G, demonstrated here for the first time in intact cells, strongly supports the hypothesis that G_i regulates GIRK gating under physiological conditions.

(Received 30 November 2006; accepted after revision 2 February 2007; first published online 8 February 2007)
Corresponding author M. Rubinstein: Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel. Email: moranrub{at}post.tau.ac.il

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