- Title
- Ca²⁺ stores regulate ryanodine receptor Ca²⁺ release channels via luminal and cytosolic Ca²⁺ sites
- Creator
- Laver, Derek R.
- Relation
- Clinical and Experimental Pharmacology and Physiology Vol. 34, Issue 9, p. 889-896
- Relation
- http://www3.interscience.wiley.com/cgi-bin/fulltext/117964545/PDFSTART
- Publisher
- Wiley-Blackwell Publishing
- Resource Type
- journal article
- Date
- 2007
- Description
- 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 [Ca²⁺] in the sarcoplasmic reticulum regulates the excitability of this store by stimulating the Ca²⁺ release channels in its membrane. This process involves Ca²⁺-sensing mechanisms on both the luminal and cytoplasmic sides of the RyR. In the cardiac RyR, these have been shown to be a luminal Ca²⁺ activation site (L-site; 60 μmol/L affinity), a cytoplasmic activation site (A-site; 0.9 μmol/L affinity) and a cytoplasmic Ca²⁺ inactivation site (I₂-site; 1.2 μmol/L affinity). 3. Cardiac RyR activation by luminal Ca²⁺ occurs by a multistep process dubbed ‘luminal-triggered Ca²⁺ feed-through’. Binding of Ca²⁺ to the L-site initiates brief (1 msec) openings at a rate of up to 10 /s. Once the pore is open, luminal Ca²⁺ 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 Ca²⁺ feed-through). 4. The present paper reviews the evidence for the principal aspects of the ‘luminal-triggered Ca²⁺ feed-through’ model, the properties of the various Ca²⁺-dependent gating mechanisms and their likely role in controlling sarcoplasmic reticulum (SR) Ca²⁺ 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 Ca²⁺ will also promote RyR activation by luminal Ca²⁺; (ii) luminal Mg²⁺ (1 mmol/L) is essential for the control of SR excitability in cardiac muscle by luminal Ca²⁺; 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 Ca²⁺ for the L-site, whereas RyR1 is not affected by luminal Mg²⁺.
- Subject
- bilayer; calcium release channels; calcium stores; cardiac muscle; excitation–contraction coupling; ryanodine
- Identifier
- http://hdl.handle.net/1959.13/44498
- Identifier
- uon:5775
- Identifier
- ISSN:1440-1681
- Language
- eng
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