Interdomain interactions within ryanodine receptors regulate Ca2+ spark frequency in skeletal muscle

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Assessment of Calcium Sparks in Intact Skeletal Muscle Fibers
11:22

Assessment of Calcium Sparks in Intact Skeletal Muscle Fibers

Published on: February 24, 2014

Alexander Shtifman1, Christopher W Ward, Takeshi Yamamoto

  • 1Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 North Greene Street, Baltimore, MD 21201, USA.

The Journal of General Physiology
|January 5, 2002
PubMed

Insights

DP4 peptide increases calcium spark frequency in muscle fibers by enhancing the opening rate of ryanodine receptors (RyR). This peptide, linked to malignant hyperthermia, preferentially binds to partially Mg2+-free RyRs, promoting channel opening.

Area of Science:

  • Molecular biology
  • Cell physiology
  • Biophysics

Background:

  • Malignant hyperthermia (MH) is a severe pharmacogenetic disorder of skeletal muscle.
  • The ryanodine receptor 1 (RyR1) is a calcium release channel implicated in MH.
  • The synthetic peptide DP4 targets a region of RyR1 associated with MH mutations.

Purpose of the Study:

  • To investigate the effects of DP4 on RyR1-mediated calcium release events.
  • To determine how DP4 influences the gating properties of RyR1.
  • To explore the role of DP4 in the context of MH.

Main Methods:

  • Laser scanning confocal microscopy of Ca2+ sparks in frog skeletal muscle fibers.
  • Measurement of [(3)H]ryanodine binding to SR vesicles.
  • Reconstitution of frog RyR1 channels in planar lipid bilayers.

Main Results:

  • DP4 significantly increased Ca2+ spark frequency in muscle fibers, indicating increased RyR opening rate.
  • DP4 increased [(3)H]ryanodine binding and RyR open probability in reconstituted channels.
  • DP4 showed a pronounced increase in channel open time in bilayers, but not in muscle fibers.
  • A mutated peptide (DP4mut) corresponding to an MH mutation did not affect RyR activation.

Conclusions:

  • DP4 enhances RyR1 activity, primarily by increasing its opening rate.
  • DP4's mechanism involves preferential binding to partially Mg2+-free RyRs.
  • These findings provide insights into RyR1 function and potential therapeutic targets for MH.

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