Regulation of RYR1 activity by Ca(2+) and calmodulin

Biochemistry. 2000 Jul 4;39(26):7807-12. doi: 10.1021/bi0005660.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calcium-Binding Proteins*
  • Calmodulin / genetics
  • Calmodulin / metabolism*
  • Drosophila Proteins*
  • EF Hand Motifs
  • Glutamic Acid / metabolism
  • In Vitro Techniques
  • Insect Proteins / metabolism
  • Mutagenesis, Site-Directed
  • Rabbits
  • Ryanodine Receptor Calcium Release Channel / drug effects
  • Ryanodine Receptor Calcium Release Channel / genetics
  • Ryanodine Receptor Calcium Release Channel / metabolism*


  • Acam protein, Drosophila
  • Calcium-Binding Proteins
  • Calmodulin
  • Drosophila Proteins
  • Insect Proteins
  • Ryanodine Receptor Calcium Release Channel
  • Glutamic Acid
  • Calcium