Ryanodine receptors as pharmacological targets for heart disease

Calcium release from intracellular stores plays an important role in the regulationof muscle contraction and electrical signals that determine the heart rhythm.Theryanodine receptor (RyR) is the major calcium (Ca2+) release channel required forexcitation-contraction coupling in the heart.Recent studies have demonstratedthat RyR are macromolecular complexes comprising of 4 pore-forming channelsubunits,each of which is associated with regulatory subunits.Clinical andexperimental studies over the past 5 years have provided compelling evidencethat intracellular Ca2+release channels play a pivotal role in the development ofcardiac arrhythmias and heart failure.Changes in the channel regulation andsubunit composition are believed to cause diastolic calcium leakage from thesarcoplasmic reticulum,which could trigger arrhythmias and weaken cardiaccontractility.Therefore,cardiac RyR have emerged as potential therapeutic tar-gets for the treatment of heart disease.Consequently,there is a strong desire toidentify and/or develop novel pharmacological agents that may target these Ca2+signaling pathways.Pharmacological agents known to modulate RyR in the heart,and their potential application towards the treatment of heart disease are dis-cussed in this review.