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Effects of the Gβ5‐RGS7 complex on muscarinic M3 receptor‐induced Ca 2+ signaling and insulin secretion (843.12)
Author(s) -
Slepak Vladlen,
KarpinskySemper Darla,
Wang Qiang
Publication year - 2014
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.28.1_supplement.843.12
Subject(s) - muscarinic acetylcholine receptor , microbiology and biotechnology , muscarinic acetylcholine receptor m3 , g protein , receptor , endocrinology , secretion , gq alpha subunit , medicine , g protein coupled receptor , muscarinic acetylcholine receptor m1 , chemistry , signal transduction , biology , biochemistry
The G protein subunit Gβ5 forms obligatory heterodimers with regulators of G protein signaling (RGS) proteins of R7 family (RGS6, 7, 9 and 11). These complexes are expressed in neurons and glands. Previously, we showed that Gβ5‐RGS7 attenuated signaling downstream of muscarinic M3 receptor, M3R. A predicted consequence of Gβ5 ablation on pancreatic beta cells would be an increase in insulin secretion. However, we found that Gβ5‐R7 knockout strongly attenuated, while its overexperession in Min6 insulinoma cells enhanced M3R‐induced insulin secretion. We studied isolated mouse islets, transfected Min6 and CHO‐K1 cells, measuring insulin secretion and changes in intracellular Ca2+ in the presence of various pharmacological agents, muscarinic agonists and functional mutants of Gβ5‐RGS7 and M3R. The results showed that Gβ5‐RGS7 has a dual effect on M3R‐mediated Ca2+ transients. While it attenuated Ca2+ release from internal stores, it stimulated Ca2+ influx across the plasma membranes. This pathway involves Gq, PLC, TRP and L‐type like Ca2+ channels, and may be particularly important in regulating secretory activity in nerve terminals and glandular cells. We also found that distinct muscarinic agonists can not only bias M3R signaling to specific pathways, but also confer differential sensitivity to the Gβ5‐RGS7 complex. Grant Funding Source : Supported by National Institutes of Health (NIH) grants RO1EY018666 and RO1GM060019