RGS Protein

Reye s Syndrome RGS Protein Rhabdomyolysis Rheumatoid Arthritis Rheumatoid Factor Rho... 

Clark MJ, Harrison C, Zhong H, et al Endogenous RGS protein action modulates mu-opioid signaling through Galphao effects on adenylyl cyclase, extracellular signal-regulated kinases, and intracellular calcium pathways. J Biol Chem 278 9418-9425, 2003... 

Spiro RG Protein glycosylation nature, distribution, en2ymatic formation, and disease implications of glycopeptide bonds. Glycobiology 2002 12 43R-... 

The large number of RGS proteins have varying degrees of selectivity for different a subunits and varying effects on different effector systems (see Vries et al., 2000). These properties are usually... 

These are just some examples of the diverse functions of RGS proteins in mammalian cells. Given the number and diversity of RGS proteins, and their region-specific expression in brain, there is considerable interest in... 

FIGURE 19-4 Schematic illustration of the structure and classification of mammalian RGS proteins. All the proteins contain a highly conserved RGS domain that has GAP activity. Most of the proteins contain additional domains that mediate other functions. The figure does not include several other types of homologous proteins, which lack the RGS domain but nevertheless are considered members of the RGS superfamily. 

The functioning of G proteins may be influenced by phosphorylation. G proteins, as well as their associated receptors and RGS proteins, have been reported to undergo phosphorylation by a host of protein serine/ threonine kinases and protein tyrosine kinases. While the ramifications of receptor phosphorylation are becoming increasingly well understood (see Chs 23 and 24), the effect of phosphorylation of G proteins and RGS proteins, and its role in the regulation of physiological processes, have been more difficult to establish with certainty. This remains an important area of future investigation. 

An increasing number of G proteins and RGS proteins have been deleted or overexpressed in genetic mutant mice. Not surprisingly, some of these mice exhibit complex behavioral abnormalities and in some cases abnormal responses to psychotropic drugs. These data further highlight the importance of G protein signaling in the brain in health and disease and open new paths for investigation in the years ahead. 

There are also many neurotransmitter and hormone receptors that contribute to the fine control of cAMP formation by inhibition of adenylyl cyclase. The action of inhibitory receptors is mediated by several different forms of the Gai family, specifically the Gail, Gai2, Gai3, Gao and Goa subtypes. The Ga subunits of these isoforms can inhibit the catalytic activity of adenylyl cyclase when the enzyme is activated by either Gas or forskolin. The inhibition of catalytic activity does not occur via competition with Gas but appears to occur by an interaction at a symmetric site on the AC molecule. Gai-mediated inhibition of adenylyl cyclase is most dramatic for AC5 and AC6. A few other forms of adenylyl cyclase, most notably AC1, can be inhibited by Gao but this effect is not as potent as the inhibition of AC5 and AC6 by Gai isoforms. The GTPase activity of Gai family members can be accelerated by a large family of RGS proteins (see Chapter 19). 

Smart EJ, Foster DC, Ying YS, Kamen BA, Anderson RG. Protein kinase C activators inhibit receptor-mediated Potocytosis by preventing internalization of caveolae. J Cell Biol 1994 124(3) 307-313. 

The process of RGS recruitment to the membrane-bound receptor, however, seems to be constitutive—it appears to be independent of the state of activation of the receptor or G protein. This recruitment may facilitate signal quenching because the combination of 30 RGS proteins and 20 Ga subunits allows for a diverse pattern of inactivation. RGS proteins, therefore, are recruited to the plasma membrane in cells expressing either Ga subunits (Gsa) or linked GPCRs (e.g., Dj-dopamine receptor) in preparation for the GAP activity that quenches G protein signaling (104,105). 

While RGS recruitment seems to be independent of the activation state of either receptor or G protein, there is evidence that RGS proteins can bind directly to GPCRs (111). It is possible that the receptors act as scaffolds serving to bring RGS proteins nearer to the G protein targets (112). Thus, RGS proteins may be selectively sorted at the plasma membrane by receptors to orient and optimize their GAP activity toward the linked Ga. 

Hepler, J. R. (2003) RGS protein and G protein interactions A httle help from their friends. Mol. Pharmacol. 64, 547-549. 

Berman DM, Gilman AG (1998) Mammalian RGS proteins barbarians at the gate. J Biol Chem 273 1269— 1272... 

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