%0 Journal Article %1 Lave_2007_889 %A Laver, Derek R %D 2007 %J Clin. Exp. Pharmacol. Physiol. %K Adenosine Animals; Biological; Calcium Calcium; Cell Channel Channel; Contraction; Cytoplasm; Gating; Humans; Ion Kinetics; Ligands; Magnesium; Membrane Models, Muscle Muscle, Myocardial Myocardium; Permeability; Receptor Release Reticulum Ryanodine Sarcoplasmic Signaling; Skeletal; Triphosphate; %N 9 %P 889--896 %R 10.1111/j.1440-1681.2007.04708.x %T Ca$^2+$ stores regulate ryanodine receptor Ca$^2+$ release channels via luminal and cytosolic Ca$^2+$ sites. %U http://dx.doi.org/10.1111/j.1440-1681.2007.04708.x %V 34 %X 1. In muscle, intracellular calcium concentration, hence skeletal muscle force and cardiac output, is regulated by uptake and release of calcium from the sarcoplasmic reticulum. The ryanodine receptor (RyR) forms the calcium release channel in the sarcoplasmic reticulum. 2. The free Ca$^2+$ in the sarcoplasmic reticulum regulates the excitability of this store by stimulating the Ca$^2+$ release channels in its membrane. This process involves Ca$^2+$-sensing mechanisms on both the luminal and cytoplasmic sides of the RyR. In the cardiac RyR, these have been shown to be a luminal Ca$^2+$ activation site (L-site; 60 micromol/L affinity), a cytoplasmic activation site (A-site; 0.9 micromol/L affinity) and a cytoplasmic Ca$^2+$ inactivation site (I2-site; 1.2 micromol/L affinity). 3. Cardiac RyR activation by luminal Ca$^2+$ occurs by a multistep process dubbed 'luminal-triggered Ca$^2+$ feed-through'. Binding of Ca$^2+$ to the L-site initiates brief (1 msec) openings at a rate of up to 10/s. Once the pore is open, luminal Ca$^2+$ has access to the A-site (producing up to 30-fold prolongation of openings) and to the I2-site (causing inactivation at high levels of Ca$^2+$ feed-through). 4. The present paper reviews the evidence for the principal aspects of the 'luminal-triggered Ca$^2+$ feed-through' model, the properties of the various Ca$^2+$-dependent gating mechanisms and their likely role in controlling sarcoplasmic reticulum (SR) Ca$^2+$ release in cardiac muscle. 5. The model makes the following important predictions: (i) there will be a close link between luminal and cytoplasmic regulation of RyRs and any cofactor that prolongs channel openings triggered by cytoplasmic Ca$^2+$ will also promote RyR activation by luminal Ca$^2+$; (ii) luminal Mg2+ (1 mmol/L) is essential for the control of SR excitability in cardiac muscle by luminal Ca$^2+$; and (iii) the different RyR isoforms in skeletal and cardiac muscle will be controlled quite differently by the luminal milieu. For example, Mg2+ in the SR lumen (approximately 1 mmol/L) can strongly inhibit RyR2 by competing with Ca$^2+$ for the L-site, whereas RyR1 is not affected by luminal Mg2+.

@article{Lave_2007_889, abstract = {1. In muscle, intracellular calcium concentration, hence skeletal muscle force and cardiac output, is regulated by uptake and release of calcium from the sarcoplasmic reticulum. The ryanodine receptor (RyR) forms the calcium release channel in the sarcoplasmic reticulum. 2. The free [{C}a$^{2+}$] in the sarcoplasmic reticulum regulates the excitability of this store by stimulating the {C}a$^{2+}$ release channels in its membrane. This process involves {C}a$^{2+}$-sensing mechanisms on both the luminal and cytoplasmic sides of the RyR. In the cardiac RyR, these have been shown to be a luminal {C}a$^{2+}$ activation site (L-site; 60 micromol/L affinity), a cytoplasmic activation site (A-site; 0.9 micromol/L affinity) and a cytoplasmic {C}a$^{2+}$ inactivation site (I2-site; 1.2 micromol/L affinity). 3. Cardiac RyR activation by luminal {C}a$^{2+}$ occurs by a multistep process dubbed 'luminal-triggered {C}a$^{2+}$ feed-through'. Binding of {C}a$^{2+}$ to the L-site initiates brief (1 msec) openings at a rate of up to 10/s. Once the pore is open, luminal {C}a$^{2+}$ has access to the A-site (producing up to 30-fold prolongation of openings) and to the I2-site (causing inactivation at high levels of {C}a$^{2+}$ feed-through). 4. The present paper reviews the evidence for the principal aspects of the 'luminal-triggered {C}a$^{2+}$ feed-through' model, the properties of the various {C}a$^{2+}$-dependent gating mechanisms and their likely role in controlling sarcoplasmic reticulum (SR) {C}a$^{2+}$ release in cardiac muscle. 5. The model makes the following important predictions: (i) there will be a close link between luminal and cytoplasmic regulation of RyRs and any cofactor that prolongs channel openings triggered by cytoplasmic {C}a$^{2+}$ will also promote RyR activation by luminal {C}a$^{2+}$; (ii) luminal Mg2+ (1 mmol/L) is essential for the control of SR excitability in cardiac muscle by luminal {C}a$^{2+}$; and (iii) the different RyR isoforms in skeletal and cardiac muscle will be controlled quite differently by the luminal milieu. For example, Mg2+ in the SR lumen (approximately 1 mmol/L) can strongly inhibit RyR2 by competing with {C}a$^{2+}$ for the L-site, whereas RyR1 is not affected by luminal Mg2+.}, added-at = {2009-06-03T11:20:58.000+0200}, author = {Laver, Derek R}, biburl = {https://www.bibsonomy.org/bibtex/2e4462a784ee34b23ca43ff34604329d1/hake}, description = {The whole bibliography file I use.}, doi = {10.1111/j.1440-1681.2007.04708.x}, file = {Lave_2007_889.pdf:Lave_2007_889.pdf:PDF}, institution = {School of Biomedical Sciences, University of Newcastle and Hunter Medical Research Institute, Callaghan, New South Wales, Australia. Derek.Laver@newcastle.edu.au}, interhash = {1832bdc9cc3ea644f28dd10511d0b747}, intrahash = {e4462a784ee34b23ca43ff34604329d1}, journal = {Clin. Exp. Pharmacol. Physiol.}, keywords = {Adenosine Animals; Biological; Calcium Calcium; Cell Channel Channel; Contraction; Cytoplasm; Gating; Humans; Ion Kinetics; Ligands; Magnesium; Membrane Models, Muscle Muscle, Myocardial Myocardium; Permeability; Receptor Release Reticulum Ryanodine Sarcoplasmic Signaling; Skeletal; Triphosphate;}, month = Sep, number = 9, pages = {889--896}, pii = {CEP4708}, pmid = {17645636}, timestamp = {2009-06-03T11:21:19.000+0200}, title = {{C}a$^{2+}$ stores regulate ryanodine receptor {C}a$^{2+}$ release channels via luminal and cytosolic {C}a$^{2+}$ sites.}, url = {http://dx.doi.org/10.1111/j.1440-1681.2007.04708.x}, volume = 34, year = 2007 }