Ryanodine receptor (RyR), a homotetrameric Ca2+ release channel, is one of the 
main actors in the generation of Ca2+ signals that trigger muscle contraction. 
Three genes encode three isoforms of RyRs, which have tissue-restricted 
distribution. RyR1 and RyR2 are typical of muscle cells, with RyR1 originally 
considered the skeletal muscle type and RyR2 the cardiac type. However, RyR1 and 
RyR2 have recently been found in numerous other cell types, including, for 
instance, peripheral B and T lymphocytes. In contrast, RyR3 is widely 
distributed among cells. RyR1 and RyR2 are localized in a specialized portion of 
the sarcoplasmic reticulum (SR), the terminal cisternae, which is the portion of 
the SR Ca2+ store that releases Ca2+ to control the process of muscle 
contraction. A specific role for RyR3 has not yet been established: probably, 
its co-expression with the other RyR isoforms contributes to qualitatively 
modulate Ca2+-dependent processes in muscle cells and in neurons. Several 
mutations in the genes encoding RyR1 and RyR2 have been identified in autosomal 
dominant diseases of skeletal and cardiac muscle, such as malignant hyperthermia 
(MH), central core disease (CCD), catecholaminergic polymorphic ventricular 
tachycardia (CPVT), and arrhythmogenic right ventricular dysplasia type 2 
(ARVD2). More recently, CCD cases with recessive inheritance have also been 
described. MH is a pharmacogenetic disease, but the others manifest as 
congenital myopathies. Even if their clinical phenotypes are well established, 
particularly in skeletal muscle, the molecular mechanisms that generate the 
conditions are not clear. A number of studies on cellular models have attempted 
to elucidate the molecular defects associated with the different mutations, but 
the problem of understanding how mutations in the same gene generate such an 
array of diverse pathological traits and diseases of widely different degrees of 
severity is still open. This review will consider the molecular and cellular 
effects of RyR mutations, summarizing recent data in the literature on Ca2+ 
dysregulation, which may lead to a better understanding of the functioning of 
RyRs.