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Received for publication July 31, 2006.
Revised January 11, 2007.
Accepted for publication January 12, 2007.
Regulator of G protein signaling (RGS) proteins modulate G protein-coupled receptor (GPCR) signaling. The N-termini of some RGS4-family proteins provide receptor specificity and also contain an N-end rule determinant that results in ubiquitylation and decreased protein expression. The relevance of these mechanisms to other RGS proteins is not fully understood. Thus we examined function, receptor specificity, and expression of R4 subfamily RGS proteins (RGS2, -3, -4, -5, and -8). While the N-terminus plays a key role in protein stability in HEK293 cells, we were unable to demonstrate specificity of RGS2, -3, -4, -5, or -8 for muscarinic receptors (M1, M3, and M5). However, cellular RGS activity (8=3>2) was strongly correlated with expression; RGS4 and 5 had minimal expression and activity. Stabilizing mutations of RGS4 and 5 (C2S) enhanced expression and function with a greater influence on RGS4 than on RGS5. Surprisingly, a predicted destabilizing mutation in RGS8 (A2C) did not markedly affect expression and had no effect on function. In contrast a destabilizing mutation in RGS2 (Q2L) recently identified as a rare N-terminal genetic variant in a Japanese hypertensive cohort (Yang et al., J Hypertens 23:1497-1505, 2005) showed significantly reduced expression and inhibition of angiotensin II (AT1) receptor-stimulated accumulation of inositol phosphates. Surprisingly, RGS2-Q2R, also predicted to be destabilizing, showed nearly normal expression and function. Thus, proteasomal regulation of RGS expression in HEK293 cells strongly controls RGS function and a novel RGS2 mutation with decreased protein expression could be relevant to the pathophysiology of hypertension in humans.
Key words:
Muscarinic cholinergic, Angiotensin, Gq/11 family, IP3/DAG, RGS proteins, Pharmacogenomic analyses, Mutagenesis/Chimeric approaches, Receptor binding studies
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