title: Coupled calcium release channels and their regulation by luminal and cytosolic ions.
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.
authors.affiliation: School of Biomedical Sciences, University of Newcastle and Hunter Medical Research Institute, Callaghan, NSW 2308, Australia. derek.laver@newcastle.edu.au
authors.forename: Derek R
authors.initials: DR
authors.lastname: Laver
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000495:Allosteric Site; D000818:Animals; D001665:Binding Sites; D001703:Biophysics / Q000379:methods*; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D015220:Calcium Channels / Q000737:chemistry*; D002412:Cations; D003593:Cytoplasm / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007477:Ions; D008051:Lipid Bilayers / Q000737:chemistry; D008274:Magnesium / Q000737:chemistry / Q000378:metabolism; D008564:Membrane Potentials; D018482:Muscle, Skeletal / Q000378:metabolism; D020033:Protein Isoforms; D012433:Ryanodine / Q000737:chemistry; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013696:Temperature
chemical_list: D015220:Calcium Channels; D002412:Cations; D007477:Ions; D008051:Lipid Bilayers; D020033:Protein Isoforms; D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; D000255:Adenosine Triphosphate; D008274:Magnesium; D002118:Calcium