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/calstabin2
(FKBP12/FKBP12.6), a 12/12.6 kDa subunit that stabilizes the closed
state of the channel and prevents aberrant calcium leak from the
SR. Kinases and phosphatases are targeted to RyR2 channels and modulate
RyR2 function in response to extracellular signals. In the classic
fight or flight stress response, phosphorylation of RyR channels
by protein kinase A reduces the affinity for calstabin and activates
the channels leading to increased SR calcium release. In heart failure,
a cardiac insult causes a mismatch between blood supply and metabolic
demands of organs. The chronically activated fight or flight response
leads to leaky channels, altered calcium signaling, and contractile
dysfunction and cardiac arrhythmias.
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