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
J. Biol. Chem.
Date: Nov. 22, 2002
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