Regulation of RYR1 activity by Ca(2+) and calmodulin.
The skeletal muscle calcium release channel (RYR1) is a Ca(2+)-binding protein that is regulated by another Ca(2+)-binding protein, calmodulin. The functional consequences of calmodulin's interaction with RYR1 are dependent on Ca(2+) concentration. At nanomolar Ca(2+) concentrations, calmodulin is an activator, but at micromolar Ca(2+) concentrations, calmodulin is an inhibitor of RYR1. This raises the question of whether the Ca(2+)-dependent effects of calmodulin on RYR1 function are due to Ca(2+) binding to calmodulin, RYR1, or both. To distinguish the effects of Ca(2+) binding to calmodulin from those of Ca(2+) binding to RYR1, a mutant calmodulin that cannot bind Ca(2+) was used to evaluate the effects of Ca(2+)-free calmodulin on Ca(2+)-bound RYR1. We demonstrate that Ca(2+)-free calmodulin enhances the affinity of RYR1 for Ca(2+) while Ca(2+) binding to calmodulin converts calmodulin from an activator to an inhibitor. Furthermore, Ca(2+) binding to RYR1 enhances its affinity for both Ca(2+)-free and Ca(2+)-bound calmodulin.
Rodney
G G
GG
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, USA.
Williams
B Y
BY
Strasburg
G M
GM
Beckingham
K
K
Hamilton
S L
SL
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D002147:Calmodulin / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins; D020832:EF Hand Motifs; D018698:Glutamic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D019476:Insect Proteins / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
C090181:Acam protein, Drosophila; D002135:Calcium-Binding Proteins; D002147:Calmodulin; D029721:Drosophila Proteins; D019476:Insect Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D018698:Glutamic Acid; D002118:Calcium