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Isolated Cardiac Ryanodine Receptor Function Varies Between Mammals.

Catherine Carvajal1, Jiajie Yan1,2, Alma Nani1

  • 1Department of Physiology & Biophysics, Section of Cellular Signaling, Rush University Medical Center, 1750 W. Harrison Avenue, Chicago, IL, 60612, USA.

The Journal of Membrane Biology
|January 29, 2024
PubMed
Summary

Cardiac ryanodine receptors (RyR2) control calcium release essential for heart function. Species differences in RyR2 function were observed in vitro, with rabbit RyR2 activity mimicking human RyR2 most closely.

Keywords:
CalsequestrinCardiac muscleRyanodine receptorSarcoplasmic reticulum

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Area of Science:

  • Cardiovascular Physiology
  • Molecular Cardiology
  • Ion Channel Biophysics

Background:

  • Cardiac ryanodine receptors (RyR2) mediate calcium (Ca2+) release from the sarcoplasmic reticulum (SR), crucial for heart contraction.
  • Abnormal RyR2 activity, specifically increased Ca2+ leak during diastole, is linked to cardiac arrhythmias like delayed afterdepolarizations (DADs).
  • Existing research highlights species-specific differences in cardiac Ca2+ handling, but in vitro RyR2 function across species remains less understood.

Purpose of the Study:

  • To investigate whether single cardiac ryanodine receptor (RyR2) function in vitro exhibits species-specific characteristics.
  • To compare the functional properties of RyR2 isolated from different mammalian species, including humans.
  • To determine which animal model's RyR2 most accurately reflects human RyR2 function in vitro.

Main Methods:

  • Isolation of RyR2-rich heavy sarcoplasmic reticulum (SR) microsomes from ventricular muscle of mouse, rat, rabbit, and human.
  • Quantification of single RyR2 function using identical in vitro solutions and electrophysiological methods.
  • Analysis of single RyR2 cytosolic Ca2+ sensitivity, mean open times, open probability, and frequency of long openings.

Main Results:

  • Single RyR2 cytosolic Ca2+ sensitivity was conserved across mouse, rat, rabbit, and human.
  • Significant species-specific differences were found in single RyR2 mean open times under both systole- and diastole-like conditions.
  • In diastole-like conditions, rat/mouse RyR2 exhibited higher open probability and frequency of long openings compared to rabbit and human RyR2.

Conclusions:

  • In vitro single RyR2 function retains species-specific attributes, likely influenced by the regulatory environment in the native tissue.
  • The functional characteristics of single rabbit RyR2, particularly under diastole-like conditions, closely resemble those of single human RyR2.
  • Rabbit RyR2 may serve as a suitable in vitro model for studying human RyR2 function in the context of diastolic Ca2+ leak and arrhythmias.