The Ryanodine Receptor: A Pivotal Ca2+ Regulatory Protein and Potential Therapeutic Drug Target

Angela F. Dulhunty, Marco Casarotto, Nicole BEARD

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

The ryanodine receptor (RyR) calcium release channel is an essential intracellular ion channel that is central to Ca(2+) signaling and contraction in the heart and skeletal muscle. The rapid release of Ca(2+) from the internal sarcoplasmic reticulum Ca(2+) stores through the RyR during excitation-contraction coupling is facilitated by the unique arrangement of the surface and sarcoplasmic reticulum membrane systems. Debilitating and sometimes fatal skeletal and cardiomyopathies result from changes in RyR activity that disrupt normal Ca(2+) signaling. Such changes can be caused by point mutations in many different regions of the RyR protein or acquired as a result of stress associated with exercise, heart failure, age or drugs. In general, both inherited and acquired changes include an increase in RyR channel activity. Because of its central function, the RyR is a potential therapeutic target for the inherited disorders and many of the acquired disorders. The RyR is currently used as a therapeutic target in malignant hyperthermia where dantrolene is effective and to relieve ventricular arrhythmia, with the use of JTV519 and flecainide. These drugs show that the RyR is a valid therapeutic target, but have side effects that prevent their chronic use. Thus there is an urgent need for the development of skeletal and cardiac specific drugs to treat these diverse muscle disorders. In this review, we discuss the mutations that cause skeletal myopathies and cardiac arrhythmias and how these mutations pinpoint residues within the RyR protein that are functionally significant and might be developed as targets for therapeutic drugs.
Original languageEnglish
Pages (from-to)709-723
Number of pages15
JournalCurrent Drug Targets
Volume12
Issue number5
DOIs
Publication statusPublished - 2011
Externally publishedYes

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Ryanodine Receptor Calcium Release Channel
Pharmaceutical Preparations
Proteins
Therapeutics
Sarcoplasmic Reticulum
Muscular Diseases
Muscle
Cardiac Arrhythmias
Flecainide
Dantrolene
Excitation Contraction Coupling
Malignant Hyperthermia
Mutation
Cardiomyopathies
Ion Channels
Point Mutation
Myocardium
Skeletal Muscle
Heart Failure
Membranes

Cite this

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abstract = "The ryanodine receptor (RyR) calcium release channel is an essential intracellular ion channel that is central to Ca(2+) signaling and contraction in the heart and skeletal muscle. The rapid release of Ca(2+) from the internal sarcoplasmic reticulum Ca(2+) stores through the RyR during excitation-contraction coupling is facilitated by the unique arrangement of the surface and sarcoplasmic reticulum membrane systems. Debilitating and sometimes fatal skeletal and cardiomyopathies result from changes in RyR activity that disrupt normal Ca(2+) signaling. Such changes can be caused by point mutations in many different regions of the RyR protein or acquired as a result of stress associated with exercise, heart failure, age or drugs. In general, both inherited and acquired changes include an increase in RyR channel activity. Because of its central function, the RyR is a potential therapeutic target for the inherited disorders and many of the acquired disorders. The RyR is currently used as a therapeutic target in malignant hyperthermia where dantrolene is effective and to relieve ventricular arrhythmia, with the use of JTV519 and flecainide. These drugs show that the RyR is a valid therapeutic target, but have side effects that prevent their chronic use. Thus there is an urgent need for the development of skeletal and cardiac specific drugs to treat these diverse muscle disorders. In this review, we discuss the mutations that cause skeletal myopathies and cardiac arrhythmias and how these mutations pinpoint residues within the RyR protein that are functionally significant and might be developed as targets for therapeutic drugs.",
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The Ryanodine Receptor: A Pivotal Ca2+ Regulatory Protein and Potential Therapeutic Drug Target. / Dulhunty, Angela F.; Casarotto, Marco; BEARD, Nicole.

In: Current Drug Targets, Vol. 12, No. 5, 2011, p. 709-723.

Research output: Contribution to journalArticle

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