Lobe-dependent regulation of ryanodine receptor type 1 by calmodulin

J Biol Chem. 2002 Oct 25;277(43):40862-70. doi: 10.1074/jbc.M206763200. Epub 2002 Aug 15.


Calmodulin activates the skeletal muscle Ca(2+) release channel RYR1 at nm Ca(2+) concentrations and inhibits the channel at microm Ca(2+) concentrations. Using a deletion mutant of calmodulin, we demonstrate that amino acids 2-8 are required for high affinity binding of calmodulin to RYR1 at both nm and microm Ca(2+) concentrations and are required for maximum inhibition of the channel at microm Ca(2+) concentrations. In contrast, the addition of three amino acids to the N terminus of calmodulin increased the affinity for RYR1 at both nm and microm Ca(2+) concentrations, but destroyed its functional effects on RYR1 at nm Ca(2+). Using both full-length RYR1 and synthetic peptides, we demonstrate that the calmodulin-binding site on RYR1 is likely to be noncontiguous, with the C-terminal lobe of both apocalmodulin and Ca(2+)-calmodulin binding to amino acids between positions 3614 and 3643 and the N-terminal lobe binding at sites that are not proximal in the primary sequence. Ca(2+) binding to the C-terminal lobe of calmodulin converted it from an activator to an inhibitor, but an interaction with the N-terminal lobe was required for a maximum effect on RYR1. This interaction apparently depends on the native sequence or structure of the first few amino acids at the N terminus of calmodulin.

Publication types

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

MeSH terms

  • Animals
  • Calmodulin / chemistry
  • Calmodulin / physiology*
  • Electrophoresis, Polyacrylamide Gel
  • Muscle, Skeletal / metabolism
  • Protein Structure, Secondary
  • Rabbits
  • Ryanodine Receptor Calcium Release Channel / metabolism
  • Ryanodine Receptor Calcium Release Channel / physiology*
  • Spectrometry, Fluorescence


  • Calmodulin
  • Ryanodine Receptor Calcium Release Channel