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.