ABSTRACT
Intracellular calcium release channels are present on sarcoplasmic and endoplasmic
reticuli (SR, ER) of all cell types. There are two classes of these channels:
ryanodine receptors (RyR) and inositol 1,4,5-trisphosphate receptors (IP3R). RyRs
are required for excitation-contraction (EC) coupling in striated (cardiac and
skeletal) muscles. RyRs are made up of macromolecular signaling complexes that
contain large cytoplasmic domains, which serve as scaffolds for proteins that
regulate the function of the channel. These regulatory proteins include calstabin1
(FKBP12) and calstabin2 (FKBP12.6), 12 kDa subunits that stabilize the closed
state of the channel and prevent aberrant calcium leak from the SR. Kinases and
phosphatases are targeted to RyR2 channels and modulate RyR2 function in
response to extracellular signals. Mutations in RyR genes have been associated
with human diseases, including malignant hyperthermia, central core disease, and
cardiac arrhythmia syndromes. In addition, defective regulation of RyRs may
contribute to abnormal intracellular calcium release in heart failure. Recent studies
in RyR and calstabin knockout mice have enhanced our understanding of the
physiological roles of these proteins in cardiac development and EC coupling.
