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

Authors
 Dong Min Shin  ;  Marlin Dehoff  ;  Shmuel Muallem  ;  Paul F. Worley  ;  Elliott M. Ross  ;  Surendra K. Nayak  ;  Jiangchen Tu  ;  Shin Hyeok Kang  ;  Xiang Luo 
Citation
 JOURNAL OF CELL BIOLOGY, Vol.162(2) : 293-303, 2003 
Journal Title
JOURNAL OF CELL BIOLOGY
ISSN
 0021-9525 
Issue Date
2003
MeSH
Animals ; Bombesin/pharmacology ; Calcium/metabolism ; Calcium/pharmacokinetics ; Calcium Signaling ; Calcium-Transporting ATPases/antagonists & inhibitors ; Calcium-Transporting ATPases/metabolism ; Carbachol/pharmacology ; Carrier Proteins/chemistry ; Carrier Proteins/genetics ; Carrier Proteins/metabolism* ; Cholecystokinin/pharmacology ; Cholinergic Agonists/pharmacology ; Enzyme Inhibitors/pharmacology ; GTP-Binding Proteins/agonists ; GTP-Binding Proteins/metabolism* ; GTPase-Activating Proteins/metabolism* ; Gene Deletion ; Homer Scaffolding Proteins ; Indoles/pharmacology ; Isoenzymes/metabolism* ; Mice ; Mice, Knockout ; Neuropeptides/chemistry ; Neuropeptides/genetics ; Neuropeptides/metabolism* ; Pancreas/cytology ; Pancreas/drug effects ; Pancreas/metabolism ; Phosphatidylinositol 4,5-Diphosphate/metabolism ; Phospholipase C beta ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; RGS Proteins/metabolism* ; Sarcoplasmic Reticulum Calcium-Transporting ATPases ; Type C Phospholipases/metabolism*
Keywords
12860966
Abstract
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 PLCβ 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 PLCβ in pancreatic acini and brain extracts and stimulated GAP activity of RGS4 and of PLCβ in an in vitro reconstitution system, with minimal effect on PLCβ-mediated PIP2 hydrolysis. These findings describe a novel, unexpected function of Homer proteins, demonstrate that RGS proteins and PLCβ 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.
Files in This Item:
T200306852.pdf Download
DOI
10.1083/jcb.200210109
Appears in Collections:
2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
Yonsei Authors
Shin, Dong Min(신동민) ORCID logo https://orcid.org/0000-0001-6042-0435
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/114551
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