Homer regulates gain of ryanodine receptor type 1 channel complex

Wei Feng, Jiancheng Tu, Tianzhong Yang, Patty Shih Vernon, Paul D. Allen, Paul F. Worley, Isaac N. Pessah

Research output: Contribution to journalArticle

Abstract

Homer proteins form an adapter system that regulates coupling of group 1 metabotropic glutamate receptors with intracellular inositol trisphosphate receptors and is modified by neuronal activity. Here, we demonstrate that Homer proteins also physically associate with ryanodine receptors type 1 (RyR1) and regulate gating responses to Ca2+, depolarization, and caffeine. In contrast to the prevailing notion of Homer function, Homer1c (long form) and Homer1-EVH1 (short form) evoke similar changes in RyR activity. The EVH1 domain mediates these actions of Homer and is selectively blocked by a peptide that mimics the Homer ligand. 1B5 dyspedic myotubes expressing RyR1 with a point mutation of a putative Homer-binding domain exhibit significantly reduced (∼33%) amplitude in their responses to K+ depolarization compared with cells expressing wild type protein. These results reveal that in addition to its known role as an adapter protein, Homer is a direct modulator of Ca2+ release gain. Homer is the first example of an "adapter" that also modifies signaling properties of its target protein. The present work reveals a novel mechanism by which Homer directly modulates the function of its target protein RyR1 and excitation-contraction coupling in skeletal myotubes. This form of regulation may be important in other cell types that express Homer and RyR1.

Original languageEnglish (US)
Pages (from-to)44722-44730
Number of pages9
JournalJournal of Biological Chemistry
Volume277
Issue number47
DOIs
StatePublished - Nov 22 2002

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Feng, W., Tu, J., Yang, T., Vernon, P. S., Allen, P. D., Worley, P. F., & Pessah, I. N. (2002). Homer regulates gain of ryanodine receptor type 1 channel complex. Journal of Biological Chemistry, 277(47), 44722-44730. https://doi.org/10.1074/jbc.M207675200