Homer regulates gain of ryanodine receptor type 1 channel complex.
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 Ca(2+), 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 (approximately 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 Ca(2+) 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.
Mesh Terms:
Animals, Binding Sites, Caffeine, Calcium, Carrier Proteins, Electrophysiology, Ligands, Lipid Bilayers, Macromolecular Substances, Muscle Contraction, Muscle, Skeletal, Mutagenesis, Site-Directed, Neuropeptides, Peptides, Potassium Chloride, Protein Binding, Rabbits, Radioligand Assay, Rats, Recombinant Fusion Proteins, Ryanodine, Ryanodine Receptor Calcium Release Channel, Sarcoplasmic Reticulum
Animals, Binding Sites, Caffeine, Calcium, Carrier Proteins, Electrophysiology, Ligands, Lipid Bilayers, Macromolecular Substances, Muscle Contraction, Muscle, Skeletal, Mutagenesis, Site-Directed, Neuropeptides, Peptides, Potassium Chloride, Protein Binding, Rabbits, Radioligand Assay, Rats, Recombinant Fusion Proteins, Ryanodine, Ryanodine Receptor Calcium Release Channel, Sarcoplasmic Reticulum
J. Biol. Chem.
Date: Nov. 22, 2002
PubMed ID: 12223488
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