Ca2+ STORES REGULATE RYANODINE RECEPTOR Ca2+ RELEASE CHANNELS VIA LUMINAL AND CYTOSOLIC Ca2+ SITES

SUMMARY 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...

Full description

Saved in:
Bibliographic Details
Published in:Clinical and experimental pharmacology & physiology 2007-09, Vol.34 (9), p.889-896
Main Author: Laver, Derek R
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Animals
bilayer
Calcium - metabolism
calcium release channels
Calcium Signaling
calcium stores
cardiac muscle
Cell Membrane Permeability
Cytoplasm - metabolism
excitation-contraction coupling
Humans
Ion Channel Gating
Kinetics
Ligands
Magnesium - metabolism
Models, Biological
Muscle Contraction
Muscle, Skeletal - metabolism
Myocardial Contraction
Myocardium - metabolism
ryanodine receptor
Ryanodine Receptor Calcium Release Channel - metabolism
Sarcoplasmic Reticulum - metabolism
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:SUMMARY 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+.
ISSN:0305-1870
1440-1681
DOI:10.1111/j.1440-1681.2007.04708.x