title: What role does modulation of the ryanodine receptor play in cardiac inotropy and arrhythmogenesis?
abstract: In this article we review the role of the Ryanodine Receptor (RyR) in cardiac inotropy and arrhythmogenesis. Most of the calcium that activates cardiac contraction comes from the sarcoplasmic reticulum (SR) from where it is released through the RyR. The amplitude of the systolic Ca transient depends steeply on the SR Ca content and it is therefore important that SR content be regulated. This regulation occurs via changes of SR Ca content affecting systolic Ca and thence sarcolemmal Ca fluxes. In the steady state, the cardiac myocyte must be in Ca flux balance on each beat and this has implications for understanding even simple inotropic manoeuvres. The main part of the review considers the effects of modulating the RyR on systolic Ca. Potentiation of RyR opening produces an increase of the amplitude of the Ca transient but this effect disappears within a few beats because the increased sarcolemmal efflux of Ca decreases SR Ca content. We conclude that it is therefore unlikely that potentiation of the RyR by phosphorylation plays a dominant role in the actions of positive inotropic agents such as beta-adrenergic stimulation. Some cardiac arrhythmias result from release of Ca from the SR in the form of waves. This is best known to occur when the SR is overloaded with calcium. Mutations in the RyR also produce cardiac arrhythmias attributed to Ca waves due to leaky RyRs and a similar leak has been suggested to contribute to arrhythmias in heart failure. We show that, due to compensatory changes of SR Ca content, simply making the RyR leaky does not produce Ca waves in the steady state and that SR Ca content is critical in determining whether Ca waves occur.
authors.affiliation: Unit of Cardiac Physiology, University of Manchester, 3.18 Core Technology Facility, Manchester, UK. Eisner@man.ac.uk
authors.forename: D A
authors.initials: DA
authors.lastname: Eisner
authors.forename: T
authors.initials: T
authors.lastname: Kashimura
authors.forename: S C
authors.initials: SC
authors.lastname: O'Neill
authors.forename: L A
authors.initials: LA
authors.lastname: Venetucci
authors.forename: A W
authors.initials: AW
authors.lastname: Trafford
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism* / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D006801:Humans; D009200:Myocardial Contraction / Q000502:physiology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium