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RGS2 gene product from candidate hypertension allele shows decreased plasma membrane association and inhibition of Gq
Author(s) -
Gu Steven,
Tirgari Sam,
Heximer Scott
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1044.5
Subject(s) - rgs2 , missense mutation , regulator of g protein signaling , mutant , allele , g protein , biology , microbiology and biotechnology , gene , mutation , chemistry , signal transduction , genetics , gtpase activating protein
Hypertension is a leading cause of mortality and morbidity in North America. Recent work has identified the Regulator of G‐protein Signaling 2(RGS2) as a candidate gene in the development of hypertension. Specifically, a single nucleotide polymorphism resulting in a missense mutation (R44H) has been correlated with hypertensive patients in a subset of the Japanese population. In our work, we identify the functional characteristics of the R44H mutation and the mechanisms by which they occur. Single cell calcium imaging shows that the mutant protein is less able to inhibit Gq signaling. Previously, we have shown that plasma membrane (PM) localization via RGS‐lipid interactions dependent on the amphipathic alpha helix is important for efficient Gq inhibition. Confocal microscopy of the R44H mutant shows greatly reduced tonic association with the PM. Finally, tryptophan spectroscopy of the helix domain shows an inability to associate with liposomes. In conclusion, we have shown that RGS2 R44H is a poor inhibitor of the M1‐muscarinic receptor and that this reduced function is a result of deficient RGS2‐lipid interactions leading to the inability to associate with the PM.