Defective Mg2+ regulation of RyR1 as a causal factor in malignant hyperthermia

Archives of Biochemistry and Biophysics
D S Steele, Adrian M Duke

Abstract

In skeletal muscle, Mg(2+) exerts a dual inhibitory effect on RyR1, by competing with Ca(2+) at the activation site and binding to a low affinity Ca(2+)/Mg(2+) inhibitory site. Pharmacological activators of RyR1 must overcome the inhibitory action of Mg(2+) before Ca(2+) efflux can occur. In normal muscle, where the free [Mg(2+)](i) is approximately 1mM, even prolonged exposure to millimolar levels of volatile anesthetics does not initiate SR Ca(2+) release. However, when the cytosolic [Mg(2+)] is reduced below the physiological range, low levels of volatile anesthetic within the clinically relevant range (1mM) can initiate SR Ca(2+) release, in the form of a propagating Ca(2+) wave. In human muscle fibers from malignant hyperthermia susceptible patients, such Ca(2+) waves occur when 1mM halothane is applied at physiological [Mg(2+)](i). There is increasing evidence to suggest that defective Mg(2+) regulation of RyR1 confers susceptibility to malignant hyperthermia. At the molecular level, interactions between critical RyR1 subdomains may explain the clustering of RyR1 mutations and associated effects on Mg(2+) regulation.

References

Apr 1, 1978·The Journal of Physiology·J R BlinksS R Taylor
Mar 1, 1991·The Journal of Physiology·G D Lamb, D G Stephenson
Jul 1, 1995·The Journal of Membrane Biology·R Sitsapesan, A J Williams
Sep 1, 1995·The Journal of Membrane Biology·D R LaverA F Dulhunty
Nov 15, 1996·The Journal of Physiology·I ParkerW G Wier
Apr 1, 1997·The Journal of Membrane Biology·D R LaverA F Dulhunty
Mar 21, 1998·Journal of the American College of Cardiology·M C HaigneyH Silverman
Dec 22, 1999·Annals of the New York Academy of Sciences·C Franzini-ArmstrongV Ramesh
Apr 15, 2000·The Journal of Biological Chemistry·T YamamotoN Ikemoto
May 10, 2001·Trends in Cardiovascular Medicine·N Ikemoto, T Yamamoto
Feb 28, 2002·Biochemical and Biophysical Research Communications·Takeshi Yamamoto, Noriaki Ikemoto
Aug 2, 1963·Science·J V BASMAJIAN
Aug 24, 2004·Proceedings of the National Academy of Sciences of the United States of America·Dawei JiangS R Wayne Chen
Sep 15, 2004·Cardiovascular Research·N Lowri ThomasF Anthony Lai
Nov 17, 2004·The Journal of General Physiology·Derek R LaverGraham D Lamb

❮ Previous
Next ❯

Citations

Jun 23, 2010·The Journal of Biological Chemistry·Adrian M DukeDerek S Steele
Aug 8, 2009·Cardiovascular Research·Lynda M BlayneyF Anthony Lai
Feb 29, 2008·American Journal of Physiology. Cell Physiology·Paula L Diaz-SylvesterJulio A Copello
Nov 21, 2008·Pharmacogenomics·Kathryn M Stowell
Nov 28, 2012·Revista brasileira de anestesiologia·Ana Carolina de Carvalho CorreiaBagnólia Araújo da Silva
Apr 5, 2017·Proceedings of the National Academy of Sciences of the United States of America·Rocky H ChoiBradley S Launikonis
Apr 27, 2017·Proceedings of the National Academy of Sciences of the United States of America·Stephen C Cannon

❮ Previous
Next ❯

Related Concepts

Related Feeds

Arrhythmogenic Right Ventricular Dysplasia

Arrhythmogenic right ventricular dysplasia is a congenital cardiomyopathy that is characterized by infiltration of adipose and fibrous tissue into the right ventricle wall and loss of myocardial cells. Primary injuries usually are at the free wall of the right ventricular and right atria resulting in ventricular and supraventricular arrhythmias. Discover the latest research on arrhythmogenic right ventricular dysplasia here.