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.
School of Biomedical Sciences, University of Newcastle and Hunter
Medical Research Institute, Callaghan, NSW 2308, Australia. derek.laver@newcastle.edu.au
%0 Journal Article
%1 Lave_2005_359
%A Laver, Derek R
%D 2005
%J Eur. Biophys. J.
%K Adenosine Allosteric Animals; Bilayers; Binding Biophysics; Calcium Calcium; Cations; Channel; Channels; Cytoplasm; Cytosol; Dose-Response Drug; Ions; Isoforms; Lipid Magnesium; Membrane Muscle, Potentials; Protein Receptor Relationship, Release Reticulum; Ryanodine Ryanodine; Sarcoplasmic Site; Sites; Skeletal; Temperature Triphosphate;
%N 5
%P 359--368
%R 10.1007/s00249-005-0483-y
%T Coupled calcium release channels and their regulation by luminal
and cytosolic ions.
%U http://dx.doi.org/10.1007/s00249-005-0483-y
%V 34
%X 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.
@article{Lave_2005_359,
abstract = {Contraction in skeletal and cardiac muscle occurs when {C}a$^{2+}$
is released from the sarcoplasmic reticulum (SR) through ryanodine
receptor (RyR) {C}a$^{2+}$ release channels. Several isoforms of
the RyR exist throughout the animal kingdom, which are modulated
by ATP, {C}a$^{2+}$ and {M}g$^{2+}$ in the cytoplasm and by {C}a$^{2+}$
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
{M}g$^{2+}$ is a potent RyR antagonist that binds to two classes
of cytoplasmic site, identified as low-affinity, non-specific inhibition
sites and high-affinity {C}a$^{2+}$ activation sites (A-sites). {M}g$^{2+}$
inhibition at the A-sites is very sensitive to the cytoplasmic and
luminal milieu. Cytoplasmic {C}a$^{2+}$, {M}g$^{2+}$ and monovalent
cations compete for the A-sites. In isolated RyRs, luminal {C}a$^{2+}$
alters the {M}g$^{2+}$ affinity of the A-site by an allosteric mechanism
mediated by luminal sites. However, in close-packed RyR arrays luminal
{C}a$^{2+}$ can also compete with cytoplasmic ions for the A-site.
Activation of RyRs by luminal {C}a$^{2+}$ has been attributed to
either {C}a$^{2+}$ feedthrough to A-sites or to {C}a$^{2+}$ regulatory
sites on the luminal side of the RyR. As yet there is no consensus
on just how luminal {C}a$^{2+}$ alters RyR activation. Recent evidence
indicates that both mechanisms operate and are likely to be important.
Allosteric regulation of A-site {M}g$^{2+}$ affinity could trigger
{C}a$^{2+}$ release, which is reinforced by {C}a$^{2+}$ feedthrough.},
added-at = {2009-06-03T11:20:58.000+0200},
author = {Laver, Derek R},
biburl = {https://www.bibsonomy.org/bibtex/21237d27c489aa6f632863f7577e92884/hake},
description = {The whole bibliography file I use.},
doi = {10.1007/s00249-005-0483-y},
institution = {School of Biomedical Sciences, University of Newcastle and Hunter
Medical Research Institute, Callaghan, NSW 2308, Australia. derek.laver@newcastle.edu.au},
interhash = {36be7284a2effedc0ba88a82b51c434f},
intrahash = {1237d27c489aa6f632863f7577e92884},
journal = {Eur. Biophys. J.},
keywords = {Adenosine Allosteric Animals; Bilayers; Binding Biophysics; Calcium Calcium; Cations; Channel; Channels; Cytoplasm; Cytosol; Dose-Response Drug; Ions; Isoforms; Lipid Magnesium; Membrane Muscle, Potentials; Protein Receptor Relationship, Release Reticulum; Ryanodine Ryanodine; Sarcoplasmic Site; Sites; Skeletal; Temperature Triphosphate;},
month = Jul,
number = 5,
pages = {359--368},
pmid = {15915341},
timestamp = {2009-06-03T11:21:19.000+0200},
title = {Coupled calcium release channels and their regulation by luminal
and cytosolic ions.},
url = {http://dx.doi.org/10.1007/s00249-005-0483-y},
volume = 34,
year = 2005
}