Abstract
Contraction in skeletal and cardiac muscle occurs when Ca$^2+$
is released from the sarcoplasmic reticulum (SR) through ryanodine
receptor (RyR) Ca$^2+$ release channels. Several isoforms of
the RyR exist throughout the animal kingdom, which are modulated
by ATP, Ca$^2+$ and Mg$^2+$ in the cytoplasm and by Ca$^2+$
in the lumen of the SR. This review brings to light recent findings
on their mechanisms of action in the mammalian isoforms RyR-1 and
RyR-2 with an emphasis on RyR-1 from skeletal muscle. Cytoplasmic
Mg$^2+$ is a potent RyR antagonist that binds to two classes
of cytoplasmic site, identified as low-affinity, non-specific inhibition
sites and high-affinity Ca$^2+$ activation sites (A-sites). Mg$^2+$
inhibition at the A-sites is very sensitive to the cytoplasmic and
luminal milieu. Cytoplasmic Ca$^2+$, Mg$^2+$ and monovalent
cations compete for the A-sites. In isolated RyRs, luminal Ca$^2+$
alters the Mg$^2+$ affinity of the A-site by an allosteric mechanism
mediated by luminal sites. However, in close-packed RyR arrays luminal
Ca$^2+$ can also compete with cytoplasmic ions for the A-site.
Activation of RyRs by luminal Ca$^2+$ has been attributed to
either Ca$^2+$ feedthrough to A-sites or to Ca$^2+$ regulatory
sites on the luminal side of the RyR. As yet there is no consensus
on just how luminal Ca$^2+$ alters RyR activation. Recent evidence
indicates that both mechanisms operate and are likely to be important.
Allosteric regulation of A-site Mg$^2+$ affinity could trigger
Ca$^2+$ release, which is reinforced by Ca$^2+$ feedthrough.
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