Using GIRK channels as ultra-sensitive detectors (nM sensitivity) for Gβγ subunits, the effect of RGS proteins on GPCR signaling can be easily observed. In heterologous cells expressing GIRK channels and a GPCR, RGS proteins accelerate both activation and deactivation rates up to 100 fold [19]. For example, RGS1 through RGS5 and RGS8 proteins accelerate both activation and deactivation kinetics of GIRK currents after stimulation of M2 muscarinic or serotonin A1 receptors [20,21]. The acceleration of deactivation kinetics agrees well with the GAP activity in the RGS. The faster rate of activation with RGS, on the other hand, is not well understood. The GAP activity of the RGS would be expected to slow, not accelerate, the rate of activation. RGS proteins will increase the pool of available G proteins, which could accelerate activation [22]. Alternatively, for GIRK channels, the formation of a receptor–G-protein–GIRK complex has been proposed to promote faster activation [20,23]. Interestingly, both RGS7 and RGS8 accelerate the activation of GIRK current but RGS8 more prominently accelerates deactivation [24]. These findings suggest that functional domains other than GAP could be involved in modulation.
