Received for publication December 12, 2007.
Revised January 23, 2008.
Accepted for publication January 23, 2008.

The RGS2 gene product from a candidate hypertension allele shows decreased plasma membrane association and inhibition of Gq

Abstract

Hypertension is a leading risk factor for the development of cardiovascular disease. Data from human and animal studies suggest that RGS2, a potent inhibitor of Gq signaling, is important for blood pressure regulation. Recently, several RGS2 mutations in the Japanese population were found to be associated with hypertension. The product of one of these alleles, R44H, is mutated within the amino terminal amphipathic alpha helix domain, the region responsible for plasma membrane-targeting. The functional consequence of this mutation and its potential link to the development of hypertension, however, are not known. Here, we show that R44H is a weaker inhibitor of receptor-mediated Gq signaling than wild type RGS2. Confocal microscopy reveals that YFP-tagged R44H binds to the plasma membrane less efficiently than wild type RGS2. R44 is one of the basic residues positioned to stabilize lipid bilayer interaction of the RGS2 amphipathic helix domain. Tryptophan fluorescence and circular dichroism studies of this domain show that the R44H mutation prevents proper entrenchment of hydrophobic residues into the lipid bilayer without disrupting helix-forming capacity. Together, these data suggest that decreasing the side chain length and flexibility at R44 prevents proper lipid bilayer association and function of RGS2. Lastly, the R44H protein does not behave as a dominant negative interfering mutant. Thus, our data are consistent with the notion that a R44H missense mutation in human RGS2 produces a hypomorphic allele that may lead to altered receptor mediated Gq-inhibition and contribute to the development of hypertension in affected individuals.

Key words: Gq/11 family, G protein regulation, RGS proteins, Ca imaging

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