RGS proteins determine signaling specificity of G(q)-coupled receptors

Xin Xu, Weizhong Zeng, Serguei Popov, David M. Berman, Isabelle Davignon, Kan Yu, David Yowe, Stefan Offermanns, Shmuel Muallem, Thomas M. Wilkie

Research output: Contribution to journalArticle

227 Scopus citations

Abstract

Regulators of G protein signaling (RGS) proteins accelerate GTP hydrolysis by Gα subunits, thereby attenuating signaling. RGS4 is a GTPase- activating protein for G(i) and G(q) class α subunits. In the present study, we used knockouts of Gq class genes in mice to evaluate the potency and selectivity of RGS4 in modulating Ca2+ signaling transduced by different G(q)-coupled receptors. RGS4 inhibited phospholipase C activity and Ca2+ signaling in a receptor-selective manner in both permeabilized cells and cells dialyzed with RGS4 through a patch pipette. Receptor-dependent inhibition of Ca2+ signaling by RGS4 was observed in acini prepared from the rat and mouse pancreas. The response of mouse pancreatic acini to carbachol was about 4- and 33-fold more sensitive to RGS4 than that of bombesin and cholecystokinin (CCK), respectively. RGS1 and RGS16 were also potent inhibitors of G(q)-dependent Ca2+ signaling and acted in a receptor- selective manner. RGS1 showed approximately 1000-fold higher potency in inhibiting carbachol than CCK-dependent signaling. RGS16 was as effective as RGS1 in inhibiting carbachol-dependent signaling but only partially inhibited the response to CCK. By contrast, RGS2 inhibited the response to carbachol and CCK with equal potency. The same pattern of receptor-selective inhibition by RGS4 was observed in acinar cells from wild type and several single and double G(q) class knockout mice. Thus, these receptors appear to couple G(q) class α subunit isotypes equally. Difference in receptor selectivity of RGS proteins action indicates that regulatory specificity is conferred by interaction of RGS proteins with receptor complexes.

Original languageEnglish (US)
Pages (from-to)3549-3556
Number of pages8
JournalJournal of Biological Chemistry
Volume274
Issue number6
DOIs
StatePublished - Feb 5 1999

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Xu, X., Zeng, W., Popov, S., Berman, D. M., Davignon, I., Yu, K., Yowe, D., Offermanns, S., Muallem, S., & Wilkie, T. M. (1999). RGS proteins determine signaling specificity of G(q)-coupled receptors. Journal of Biological Chemistry, 274(6), 3549-3556. https://doi.org/10.1074/jbc.274.6.3549