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Homer 2 tunes G protein-coupled receptors stimulus intensity by regulating RGS proteins and PLCbeta GAP activities.

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 PLCbeta 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 PLCbeta in pancreatic acini and brain extracts and stimulated GAP activity of RGS4 and of PLCbeta in an in vitro reconstitution system, with minimal effect on PLCbeta-mediated PIP2 hydrolysis. These findings describe a novel, unexpected function of Homer proteins, demonstrate that RGS proteins and PLCbeta 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.

Pubmed ID: 12860966


  • Shin DM
  • Dehoff M
  • Luo X
  • Kang SH
  • Tu J
  • Nayak SK
  • Ross EM
  • Worley PF
  • Muallem S


The Journal of cell biology

Publication Data

July 21, 2003

Associated Grants


Mesh Terms

  • Animals
  • Bombesin
  • Calcium
  • Calcium Signaling
  • Calcium-Transporting ATPases
  • Carbachol
  • Carrier Proteins
  • Cholecystokinin
  • Cholinergic Agonists
  • Enzyme Inhibitors
  • GTP-Binding Proteins
  • GTPase-Activating Proteins
  • Gene Deletion
  • Indoles
  • Isoenzymes
  • Mice
  • Mice, Knockout
  • Neuropeptides
  • Pancreas
  • Phosphatidylinositol 4,5-Diphosphate
  • Phospholipase C beta
  • Protein Isoforms
  • RGS Proteins
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Type C Phospholipases