Heterotrimeric G proteins function as molecular relays, shuttling between cell surface receptors and intracellular effectors that propagate a signal. G protein signaling is governed by the rates of GTP binding (catalyzed by the receptor) and GTP hydrolysis. RGS proteins (regulators of G protein signaling) were identified as potent negative regulators of G protein signaling pathways in simple eukaryotes and are now known to act as GTPase-activating proteins (GAPs) for G protein ␣-subunits in vitro. It is not known, however, if G␣ GAP activity is responsible for the regulatory action of RGS proteins in vivo. We describe here a G␣ mutant in yeast (gpa1 sst ) that phenotypically mimics the loss of its cognate RGS protein (SST2). The gpa1 sst mutant is resistant to an activated allele of SST2 in vivo and is unresponsive to RGS GAP activity in vitro. The analogous mutation in a mammalian G q ␣ is also resistant to RGS action in transfected cells. These mutants demonstrate that RGS proteins act through G␣ and that RGS-GAP activity is responsible for their desensitizing activity in cells. The G␣ sst mutant will be useful for uncoupling RGS-mediated regulation from other modes of signal regulation in whole cells and animals.A wide variety of cellular signals (hormones, neurotransmitters, light, odors) act through a three component system composed of cell surface receptors, heterotrimeric G proteins, and effector proteins (1). The mating pheromones in yeast Saccharomyces cerevisiae act through receptors (STE2, STE3 gene products), a G protein ␣␤␥ heterotrimer (GPA1, STE4, STE18), and a mitogen-activated protein kinase signaling cascade that promotes cell division arrest and fusion (2). If mating is unsuccessful, however, the cells become refractory to pheromone stimulation and will eventually resume normal growth. RGS1 proteins have recently been identified as a fourth component of the G protein signaling pathway (2, 3). The founding member of the RGS family, called SST2, was identified in a genetic screen for negative regulators of the pheromone response pathway in yeast (4). Loss of function sst2 mutants render cells supersensitive to a pheromone stimulus and unable to recover from pheromone-induced growth arrest. Dominant gain-of-function alleles of SST2 have the opposite effect, rendering cells insensitive to pheromone stimulation (5). Further genetic and biochemical experiments revealed that Sst2 interacts directly with the G protein ␣-subunit, Gpa1 (6).Behavioral genetic analyses in C. elegans uncovered a homologue of Sst2, called EGL-10 (7). egl-10 was shown to negatively regulate goa-1, which encodes the G␣ that mediates serotonindependent egg laying behavior. Two mammalian homologues, GAIP and RGS10, were identified by their interaction with G␣-subunits in a two-hybrid screen (8, 9). An additional 15 mammalian members of the family were found by expression cloning, degenerate polymerase chain reaction, low stringency hybridization, and as expressed sequence tags (7-11). All of the RGS proteins share a conserved "...

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Despite the recent blossoming of rigorous research into placebo mechanisms and the long-standing use of placebos in clinical trials, there remains widespread and profound misunderstanding of the placebo response among both practicing physicians and clinical researchers. This review identifies and clarifies areas of current confusion about the placebo response (including whether it exists at all), describes its phenomenology, and outlines recent advances in our knowledge of its underlying psychological and neural mechanisms. The focus of the review is the placebo analgesic response rather than placebo responses in general, because much of the best established clinical and experimental work to date has been done on this type of placebo response. In addition, this subfield of placebo research offers a specific neural circuit hypothesis capable of being integrated with equally rigorous experimental work on the psychological (including social psychological) and clinical levels. In this sense, placebo analgesia research bears all the marks of a genuine multilevel interdisciplinary research paradigm in the making, one that could serve as a model for research into other kinds of placebo responses, as well as into other kinds of mind-body responses.

Regulators of G protein signaling (RGS proteins)

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