Transient elevations of intracellular Ca2+ play a signalling role in such 
complex cellular functions as contraction, secretion, fertilization, 
proliferation, metabolism, heartbeat and memory. However, prolonged elevation of 
Ca2+ above about 10 microM is deleterious to a cell and can activate apoptosis. 
In muscle, there is a narrow window of Ca2+ dysregulation in which abnormalities 
in Ca2+ regulatory proteins can lead to disease, rather than apoptosis. Key 
proteins in the regulation of muscle Ca2+ are the voltage-dependent, 
dihydropyridine-sensitive, L-type Ca2+ channels located in the transverse tubule 
and Ca2+ release channels in the junctional terminal cisternae of the 
sarcoplasmic reticulum. Abnormalities in these proteins play a key role in 
malignant hyperthermia (MH), a toxic response to anesthetics, and in central 
core disease (CCD), a muscle myopathy. Sarco(endo)plasmic reticulum Ca2+ ATPases 
(SERCAs) return sarcoplasmic Ca2+ to the lumen of the sarcoplasmic reticulum. 
Loss of SERCA1a Ca2+ pump function is one cause of exercise-induced impairment 
of the relaxation of skeletal muscle, in Brody disease. Phospholamban expressed 
in cardiac muscle and sarcolipin expressed in skeletal muscle regulate SERCA 
activity. Studies with knockout and transgenic mice show that gain of inhibitory 
function of phospholamban alters cardiac contractility and could be a causal 
feature in some cardiomyopathies. Calsequestrin, calreticulin, and a series of 
other acidic, lumenal, Ca2+ binding proteins provide a buffer for Ca2+ stored in 
the sarcoplasmic reticulum. Overexpression of cardiac calsequestrin leads to 
cardiomyopathy and ablation of calreticulin alters cardiac development.