From the ryanodine receptor to cardiac arrhythmias.
Cardiac contraction is activated by an increase of intracellular calcium concentration ([Ca(2+)](i)), most of which comes from the sarcoplasmic reticulum (SR) where it is released, via the ryanodine receptor (RyR), in response to Ca(2+) entering the cell on the L-type Ca(2+) current. This phenomenon is termed Ca(2+)-induced Ca(2+) release (CICR). However, under certain circumstances, the SR can become overloaded with Ca(2+) and once a threshold SR Ca(2+) content is reached Ca(2+) is released spontaneously. Such spontaneous Ca(2+) release from the SR propagates as a Ca(2+) wave by CICR. Some of the Ca(2+) released during a wave is removed from the cell on the electrogenic Na - Ca exchanger resulting in depolarization. This is the cellular mechanism producing delayed afterdepolarizations and is common to those arrhythmias produced by digitalis toxicity and right ventricular outflow tract tachycardia. More recently it has been suggested that arrhythmogenic Ca(2+) waves can also occur if the properties of the RyR are altered, resulting in increase of RyR open probability, for example by phosphorylation. However, in this review experimental evidence will be presented to support the view that such arrhythmias still require a threshold SR Ca(2+) content to be exceeded and that this threshold is decreased by increasing RyR open probability.
Eisner
D A
DA
Manchester Academic Health Science Centre, The University of Manchester, Core Technology Facility, Manchester, UK. Eisner@man.ac.uk
Kashimura
T
T
Venetucci
L A
LA
Trafford
A W
AW
D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D006801:Humans; D015640:Ion Channel Gating; D009200:Myocardial Contraction / Q000187:drug effects; D010766:Phosphorylation; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism
D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel; D019831:Sodium-Calcium Exchanger