Single-cell imaging of intracellular Ca2+ and phospholipase C activity reveals that RGS 2, 3, and 4 differentially regulate signaling via the Galphaq/11-linked muscarinic M3 receptor

Molecular Pharmacology
Stephen C Tovey, Gary B Willars

Abstract

Using single cell, real-time imaging, this study compared the impact of members of the B/R4 subfamily of the regulators of G-protein signaling (RGS) (RGS2, -3, and -4) on receptor-mediated inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], diacylglycerol, and Ca2+ signaling. In human embryonic kidney (HEK) 293 cells expressing recombinant Galpha(q/11)-coupled muscarinic M3 receptors, transient coexpression of RGS proteins with fluorescently-tagged biosensors for either Ins(1,4,5)P3 or diacylglycerol demonstrated that RGS2 and 3 inhibited receptor-mediated events. Although gross indices of signaling were unaffected by RGS4, it slowed the rate of increase in Ins(1,4,5)P3 levels. At equivalent levels of expression, myc-tagged RGS proteins showed inhibitory activity on the order RGS3 > or = RGS2 > RGS4. In HEK293 cells, stable expression of myc-tagged RGS2, -3, or -4 at equivalent levels also inhibited phosphoinositide and Ca2+ signaling by endogenously expressed muscarinic M3 receptors in the order RGS3 > or = RGS2 > RGS4. In these cells, RGS2 or -3 reduced receptor-mediated inositol phosphate generation in cell populations and reduced both the magnitude and kinetics (rise-time) of single cell Ca2+ signals. Furthermore, at low levels of...Continue Reading

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Citations

Nov 15, 2011·Proceedings of the National Academy of Sciences of the United States of America·Neil S HoldenRobert Newton
Jun 15, 2007·Pharmacogenetics and Genomics·Lior GreenbaumBernard Lerer
May 8, 2009·The Journal of Pharmacology and Experimental Therapeutics·Nisha KurianGary B Willars
Sep 29, 2006·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Daniela BillupsStefan R Nahorski
Jun 16, 2012·Current Opinion in Neurobiology·S FaumontS R Lockery
May 12, 2006·Seminars in Cell & Developmental Biology·Gary B Willars
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