A central core disease mutation in the Ca2+-binding site of skeletal muscle ryanodine receptor impairs single-channel regulation

Venkat R. Chirasani, Le Xu, Hannah G. Addis, Daniel A. Pasek, Nikolay V. Dokholyan, Gerhard Meissner, Naohiro Yamaguchi

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Cryoelectron microscopy and mutational analyses have shown that type 1 ryanodine receptor (RyR1) amino acid residues RyR1-E3893,-E3967, and-T5001 are critical for Ca2+-mediated activation of skeletal muscle Ca2+ release channel. De novo missense mutation RyR1-Q3970K in the secondary binding sphere of Ca2+ was reported in association with central core disease (CCD) in a 2-yr-old boy. Here, we characterized recombinant RyR1-Q3970K mutant by cellular Ca2+ release measurements, single-channel recordings, and computational methods. Caffeine-induced Ca2+ release studies indicated that RyR1-Q3970K formed caffeine-sensitive, Ca2+-con-ducting channel in HEK293 cells. However, in single-channel recordings, RyR1-Q3970K displayed low Ca2+-dependent channel activity and greatly reduced activation by caffeine or ATP. A RyR1-Q3970E mutant corresponds to missense mutation RyR2-Q3925E associated with arrhythmogenic syndrome in cardiac muscle. RyR1-Q3970E also formed caffeine-induced Ca2+ release in HEK293 cells and exhibited low activity in the presence of the activating ligand Ca2+ but, in contrast to RyR1-Q3970K, was activated by ATP and caffeine in single-channel recordings. Computational analyses suggested distinct structural rearrangements in the secondary binding sphere of Ca2+ of the two mutants, whereas the interaction of Ca2+ with directly interacting RyR1 amino acid residues Glu3893, Glu3967, and Thr5001 was only minimally affected. We conclude that RyR1-Q3970 has a critical role in Ca2+-dependent activation of RyR1 and that a missense RyR1-Q3970K mutant may give rise to myopathy in skeletal muscle.

Original languageEnglish (US)
Pages (from-to)C358-C365
JournalAmerican Journal of Physiology - Cell Physiology
Issue number2
StatePublished - Aug 2019

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cell Biology


Dive into the research topics of 'A central core disease mutation in the Ca<sup>2+</sup>-binding site of skeletal muscle ryanodine receptor impairs single-channel regulation'. Together they form a unique fingerprint.

Cite this