In excitable cells such as skeletal and cardiac myocytes excitation-contraction 
coupling is an important intermediate step between initiation of the action 
potential and induction of contraction. This process is predominantly controlled 
by Ca(2+) release from the sarcoplasmic reticulum via the ryanodine receptor. 
This very large protein (MW 560 kDa) exists as a homotetramer (~2.2 MDa) and is 
expressed in three isoforms: RyR1, expressed in skeletal muscle; RyR2, expressed 
in cardiac muscle; and RyR3, expressed in various cells at lower levels than the 
other isoforms. Release of Ca(2+) via RyR2 is induced by Ca(2+) influx through 
L-type Ca(2+) channels and is modulated by multiple factors, including 
phosphorylation of RyR2 protein by protein kinase A, calmodulin kinase II and 
FKBP12.6, and stimulation via the beta-adrenergic receptor signaling pathway. 
Hyperphosphorylation of RyR2 induces Ca(2+) leak during diastole, which can 
cause fatal arrhythmias and lead to heart failure. This makes RyR2 an important 
therapeutic target. Although there are few commercially available drugs that 
inhibit Ca(2+) leak from RyR2, K201 (JTV-519), a benzothiazepine derivative, has 
emerged as a new ryanodine receptor-selective agent that prevents atrial 
fibrillation, ventricular arrhythmias, heart failure and exercise-induced sudden 
cardiac death. In this review, we discuss recent advances in our understanding 
of the basic structure and function of ryanodine receptors, their involvement in 
heart disease, and the development of drugs to prevent ryanodine receptor 
malfunction and recent patents.