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

Dong Min Shin, Marlin Dehoff, Xiang Luo, Shin Hyeok Kang, Jiangchen Tu, Surendra K. Nayak, Elliott M. Ross, Paul E. Worley, Shmuel Muallem

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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.

Original languageEnglish
Pages (from-to)293-303
Number of pages11
JournalJournal of Cell Biology
Volume162
Issue number2
DOIs
Publication statusPublished - 2003 Jul 21

All Science Journal Classification (ASJC) codes

  • Cell Biology

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    Shin, D. M., Dehoff, M., Luo, X., Kang, S. H., Tu, J., Nayak, S. K., Ross, E. M., Worley, P. E., & Muallem, S. (2003). Homer 2 tunes G protein-coupled receptors stimulus intensity by regulating RGS proteins and PLCβ GAP activities. Journal of Cell Biology, 162(2), 293-303. https://doi.org/10.1083/jcb.200210109