Vesl/Homer proteins regulate ryanodine receptor type 2 function and intracellular calcium signaling

• Published in: Cell calcium (Edinburgh) 2003-09, Vol.34 (3), p.261-269
• Main Authors: Westhoff, Jens H, Hwang, Sung-Yong, Scott Duncan, R, Ozawa, Fumiko, Volpe, Pompeo, Inokuchi, Kaoru, Koulen, Peter
• Format: Article
• Language: English
• Subjects: Aniline Compounds - analysis; Aniline Compounds - metabolism; Animals; Binding Sites - genetics; Blotting, Western - methods; Caffeine - pharmacology; Calcium - analysis; Calcium - metabolism; Calcium release; Calcium Signaling - physiology; Carrier Proteins - pharmacology; Carrier Proteins - physiology; Central nervous system; CHO Cells; Cricetinae; Cyclic ADP-Ribose - pharmacology; Dantrolene - pharmacology; Dose-Response Relationship, Drug; Egtazic Acid - analogs & derivatives; Egtazic Acid - pharmacology; Electrophysiology; Heart muscle; Homer Scaffolding Proteins; Immunochemistry; Intracellular calcium stores; Microscopy, Fluorescence; Myocardium - metabolism; Neuropeptides - pharmacology; Neuropeptides - physiology; Planar lipid bilayer; Protein Binding; Protein Isoforms - pharmacology; Protein Isoforms - physiology; Rat; Rats; Ryanodine - pharmacology; Ryanodine Receptor Calcium Release Channel - genetics; Ryanodine Receptor Calcium Release Channel - physiology; Sarcoplasmic Reticulum - drug effects; Sarcoplasmic Reticulum - metabolism; Transfection; Xanthenes - analysis; Xanthenes - metabolism
• ISSN: 0143-4160; 1532-1991
• DOI: 10.1016/S0143-4160(03)00112-X

Cellular signaling proteins such as metabotropic glutamate receptors, Shank, and different types of ion channels are physically linked by Vesl ( VASP/ Ena-related gene up-regulated during seizure and LTP)/Homer proteins [Curr. Opin. Neurobiol. 10 (2000) 370; Trends Neurosci. 23 (2000) 80; J. Cell Sci. 113 (2000) 1851]. Vesl/Homer proteins have also been implicated in differentiation and physiological adaptation processes [Nat. Neurosci. 4 (2001) 499; Nature 411 (2001) 962; Biochem. Biophys. Res. Commun. 279 (2000) 348]. Here we provide evidence that a Vesl/Homer subtype, Vesl-1L/Homer-1c (V-1L), reduces the function of the intracellular calcium channel ryanodine receptor type 2 (RyR2). In contrast, Vesl-1S/Homer-1a (V-1S) had no effect on RyR2 function but reversed the effects of V-1L. In live cells, in calcium release studies and in single-channel electrophysiological recordings of RyR2, V-1L reduced RyR2 activity. Important physiological functions and pharmacological properties of RyR2 are preserved in the presence of V-1L. Our findings demonstrate that a protein–protein interaction between V-1L and RyR2 is not only necessary for organizing the structure of intracellular calcium signaling proteins [Curr. Opin. Neurobiol. 10 (2000) 370; Trends Neurosci. 23(2000)80; J. Cell Sci. 113 (2000) 1851; Nat Neurosci. 4 (2001) 499; Nature 411 (2001) 962; Biochem. Biophys. Res. Commun. 279 (2000) 348; Nature 386 (1997) 284], but that V-1L also directly regulates RyR2 channel activity by changing its biophysical properties. Thereby it may control cellular calcium homeostasis. These observations suggest a novel mechanism for the regulation of RyR2 and calcium-dependent cellular functions.