Vesl/Homer proteins regulate ryanodine receptor type 2 function and intracellular calcium signaling.
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.
Westhoff
Jens H
JH
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA.
Hwang
Sung-Yong
SY
Duncan
R Scott
RS
Ozawa
Fumiko
F
Volpe
Pompeo
P
Inokuchi
Kaoru
K
Koulen
Peter
P
D000814:Aniline Compounds / Q000032:analysis / Q000378:metabolism; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western / Q000379:methods; D016466:CHO Cells; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000032:analysis / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D002352:Carrier Proteins / Q000494:pharmacology / Q000502:physiology*; D006224:Cricetinae; D036563:Cyclic ADP-Ribose / Q000494:pharmacology; D003620:Dantrolene / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004594:Electrophysiology; D000072233:Homer Scaffolding Proteins; D008856:Microscopy, Fluorescence; D009206:Myocardium / Q000378:metabolism; D009479:Neuropeptides / Q000494:pharmacology / Q000502:physiology*; D011485:Protein Binding; D020033:Protein Isoforms / Q000494:pharmacology / Q000502:physiology; D051381:Rats; D012433:Ryanodine / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D014162:Transfection; D014966:Xanthenes / Q000032:analysis / Q000378:metabolism
D000814:Aniline Compounds; D002352:Carrier Proteins; D000072233:Homer Scaffolding Proteins; D009479:Neuropeptides; D020033:Protein Isoforms; D019837:Ryanodine Receptor Calcium Release Channel; D014966:Xanthenes; D036563:Cyclic ADP-Ribose; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D012433:Ryanodine; C059715:Fluo-3; D002110:Caffeine; D004533:Egtazic Acid; D003620:Dantrolene; D002118:Calcium