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Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
N-terminally green fluorescent protein (GFP)-tagged regulator of G protein signaling (RGS) 2 and RGS4 fusion proteins expressed in human embryonic kidney 293 cells localized to the nucleus and cytosol, respectively. They were selectively recruited to the plasma membrane by G proteins and correspondingly by receptors that activate those G proteins: GFP-RGS2 when coexpressed with G
s, 
2-adrenergic receptor, Gq, or AT1A angiotensin II receptor, and GFP-RGS4 when coexpressed with Gi2 or M2 muscarinic receptor. G protein mutants with reduced RGS affinity did not produce this effect, implying that the recruitment involves direct binding to G proteins and is independent of downstream signaling events. Neither agonists nor inverse agonists altered receptor-promoted RGS association with the plasma membrane, and expressing either constitutively activated or poorly activated G protein mutants produced effects similar to those of their wild-type counterparts. Thus, intracellular interactions between these proteins seem to be relatively stable and insensitive to the activation state of the G protein, in contrast to the transient increases in RGS-G protein association known to be caused by G protein activation in solution-based assays. G protein effects on RGS localization were mirrored by RGS effects on G protein function. RGS4 was more potent than RGS2 in promoting steady-state Gi GTPase activity, whereas RGS2 inhibited Gs-dependent increases in intracellular cAMP, suggesting that G protein signaling in cells is regulated by the selective recruitment of RGS proteins to the plasma membrane.
Address correspondence to: Peter Chidiac, Ph.D., Department of Physiology and Pharmacology, Medical Sciences Building, University of Western Ontario, London, Ontario N6A 5C1, Canada. E-mail: peter.chidiac{at}fmd.uwo.ca
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