JCB logo
PeproTech: Cell Culture Supplements
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
Published online 14 July 2003. doi:10.1083/jcb.200210109
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 330K)
Right arrow PPT slides of all figures
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JCB
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Shin, D. M.
Right arrow Articles by Muallem, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shin, D. M.
Right arrow Articles by Muallem, S.
Right arrowPubmed/NCBI databases
*Gene*GEO Profiles
*HomoloGene*Protein
*UniGene
*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*CALCIUM COMPOUNDS
*CALCIUM, ELEMENTAL
*CARBACHOL CHLORIDE
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

© 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.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:



  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents