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Published online 14 July 2003. doi:10.1083/jcb.200210109
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© The Rockefeller University Press, 0021-9525/2003/7/293 $5.00
The Journal of Cell Biology, Volume 162, Number 2, 293-303

Article

Homer 2 tunes G protein–coupled receptors stimulus intensity by regulating RGS proteins and PLCß GAP activities



Dong Min Shin1, Marlin Dehoff2, Xiang Luo4, Shin Hyeok Kang2, Jiangchen Tu2, Surendra K. Nayak5, Elliott M. Ross5, Paul F. Worley2,3 and Shmuel Muallem4

1 Department of Oral Biology, Brain Korea 21 Project of Medical Sciences, Yonsei University, Seoul 120-752, South Korea
2 Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287
3 Department of Neurology/Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287
4 Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390
5 Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390

Address correspondence to Shmuel Muallem, Dept. of Physiology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75235-9040. Tel.: (214) 648-2593. Fax: (214) 648-8879. E-mail: Shmuel.Muallem{at}UTSouthwestern.edu; or Paul F. Worley, 600 North Wolfe St., Baltimore, MD 21205. Tel.: (410) 502-5489. Fax: (410) 614-8423. E-mail: pworley{at}jhmi.edu

Homers are scaffolding proteins that bind G protein–coupled receptors (GPCRs), inositol 1,4,5-triphosphate (IP3) receptors (IP3Rs), ryanodine receptors, and TRP channels. However, their role in Ca2+ signaling in vivo is not known. Characterization of Ca2+ signaling in pancreatic acinar cells from Homer2-/- and Homer3-/- mice showed that Homer 3 has no discernible role in Ca2+ signaling in these cells. In contrast, we found that Homer 2 tunes intensity of Ca2+ signaling by GPCRs to regulate the frequency of [Ca2+]i oscillations. Thus, deletion of Homer 2 increased stimulus intensity by increasing the potency for agonists acting on various GPCRs to activate PLCß and evoke Ca2+ release and oscillations. This was not due to aberrant localization of IP3Rs in cellular microdomains or IP3R channel activity. Rather, deletion of Homer 2 reduced the effectiveness of exogenous regulators of G proteins signaling proteins (RGS) to inhibit Ca2+ signaling in vivo. Moreover, Homer 2 preferentially bound to PLCß in pancreatic acini and brain extracts and stimulated GAP activity of RGS4 and of PLCß in an in vitro reconstitution system, with minimal effect on PLCß-mediated PIP2 hydrolysis. These findings describe a novel, unexpected function of Homer proteins, demonstrate that RGS proteins and PLCß GAP activities are regulated functions, and provide a molecular mechanism for tuning signal intensity generated by GPCRs and, thus, the characteristics of [Ca2+]i oscillations.

Key Words: Homers; GPCR; Ca2+ signaling; regulation; IP3

D.M. Shin, M. Dehoff, and X. Luo contributed equally to this work.

* Abbreviations used in this paper: BS, bombesin; CPA, cyclopiazonic acid; GAP, GTPase-activating protein; GPCR, G protein–coupled receptors; IP3, inositol 1,4,5-triphosphate; IP3R, IP3 receptor; pAb, polyclonal antibody; PIP2, phosphatidylinositol-bisphosphate; PMCA, plasma membrane Ca2+ ATPase; RGS, regulators of G proteins signaling; SERCA, sarco/endoplasmic reticulum Ca2+ ATPase; SLO, streptolysin O; WT, wild-type.


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