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Ryanodine receptor

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ryanodine receptor 1 (skeletal)
Symbol(s): RYR1 MHS, MHS1, CCO
Locus: 19 q13.1
EC number [1]
EntrezGene 6261
OMIM 180901
RefSeq NM_000540
UniProt P21817
ryanodine receptor 2 (cardiac)
Symbol(s): RYR2
Locus: 1 q42.1 -q43
EC number [2]
EntrezGene 6262
OMIM 180902
RefSeq NM_001035
UniProt Q92736
ryanodine receptor 3
Symbol(s): RYR3
Locus: 15 q14 -q15
EC number [3]
EntrezGene 6263
OMIM 180903
RefSeq NM_001036
UniProt Q15413

Ryanodine receptors (RyRs) form a class of calcium channels in various forms of muscle and other excitable animal tissue. It is the major cellular mediator of calcium induced calcium release (CICR) in animal cells.

EtymologyEdit

The receptors are named after the plant alkaloid ryanodine, to which they show high affinity:

IsoformsEdit

There are multiple isoforms of ryanodine receptors:

  • RyR1 is expressed in skeletal muscle,
  • RyR2 in myocardium (heart muscle).
  • A third form, RyR3, is expressed more widely, but especially in the brain[1].
  • There is also a fourth form found only in fish.

PhysiologyEdit

Ryanodine receptors mediate the release of calcium ions from the sarcoplasmic reticulum, an essential step in muscle contraction. In skeletal muscle, it is thought that activation occurs via a physical coupling to the L-type calcium channel, while in cardiac muscle, the primary mechanism is calcium-induced calcium release [2].

It has been shown that calcium release from a number of ryanodine receptors in a ryanodine receptor cluster results in a spatiotemporally-restricted rise in cytosolic calcium that can be visualised as a calcium spark [3].

Ryanodine receptors are similar to the inositol triphosphate (IP3) receptor and stimulated to transport Ca2+ into the cytosol by recognizing Ca2+ on its cytosolic side, thus establishing a positive feedback mechanism; a small amount of Ca2+ in the cytosol near the receptor will cause it to release even more Ca2+ (calcium-induced calcium release/CICR).[1]

RyRs are especially important in neurons and muscle cells. In heart and pancreas cells, another second messenger (cyclic ADP ribose) takes part in the receptor activation.

The localized and time-limited activity of Ca2+ in the cytosol is also called a Ca2+ wave. The building of the wave is done by

  • the feedback mechanism of the ryanodine receptor and
  • the activation of phospholipase C by GPCR or TRK, which leads to the production of inositol triphosphate, which in turn activates the InsP3 receptor.

PharmacologyEdit

  • Activators:[5]
    • Agonist: 4-chloro-m-cresol and suramin are direct agonists ie direct activators.
    • Xanthines like caffeine and pentifylline activates it by potentiating sensitivity to native ligand Ca.
      • Physiological agonist: cADPR can act as a physiological gating agent. It has been suggested that it may act by making FKBP12.6 (12.6 kilodalton FK506 binding protein, as opposed to 12kd FKBP12 which binds to RyR1) which normally bind (and blocks) RyR2 channel tetramer in an average stoichiometry of 3.6, to fall off RyR2 (which is the predominant RyR in pancreatic beta cells, cardiomyocytes and smooth muscles).[6]

A variety of other molecules may interact with and regulate Ryanodine receptor. For example: Dimerized Homer physical tether linking inositol trisphosphate receptors (IP3R) and ryanodine receptors on the intracellular calcium stires with cell surface group 1 metabotropic Glutamate Receptors and the alpha 1D adrenergic receptor[7]

RyanodineEdit

The plant alkaloid ryanodine, for which this receptor was named, has become an invaluable investigative tool. It can block the phasic release of calcium, but at low doses may not block the tonic cumulative calcium release. The binding of ryanodine to RyRs is ‘use-dependent’, that is the channels have to be in the activated state. At low (<10 MicroMolar, works even at nanomolar) concentrations, ryanodine binding locks the RyRs into a long-lived subconductance (half open) state and eventually depletes the store, while higher (~100 MicroMolar) concentrations irreversibly inhibit channel opening.

CaffeineEdit

RyRs are activated by millimolar caffeine concentrations. High (greater than 5 millimolar) caffeine concentrations cause a pronounced increase (from micromolar to picomolar) in the sensitivity of RyRs to Ca2+ in the presence of caffeine, such that basal Ca2+ concentrations become activatory. At low millimolar caffeine concentrations the receptor opens in a quantal way but has complicated behavior in terms of repeated use of caffeine or dependence on cytosolic or luminal calcium concentrations.

Role in diseaseEdit

RyR1 mutations are associated with malignant hyperthermia and central core disease. RyR2 mutations play a role in stress-induced polymorphic ventricular tachycardia (a form of cardiac arrhythmia) and ARVD.[1] It has also been shown that levels of type RyR3 are greatly increased in PC12 cells overexpressing mutant human Presenilin 1, and in brain tissue in knockin mice that express mutant Presenilin 1 at normal levels, and thus may play a role in the pathogenesis of neurodegenerative diseases, like Alzheimer's disease.

The presence of antibodies against ryanodine receptors in blood serum has also been associated with myasthenia gravis.

ReferenceEdit

  1. 1.0 1.1 1.2 Zucchi R, Ronca-Testoni S. The sarcoplasmic reticulum Ca2+ channel/ryanodine receptor: modulation by endogenous effectors, drugs and disease states. Pharmacol Rev 1997;49:1-51. PMID 9085308.
  2. Fabiato A (1983). Calcium-induced calcium release of calcium from the cardiac sarcoplasmic reticulum. Am J Physiol 245 (1): C1-C14.
  3. Cheng H, Lederer WJ, Cannell MB (1993). Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle. Science 262 (5134): 740-744.
  4. Vites A, Pappano A (1994). Distinct modes of inhibition by ruthenium red and ryanodine of calcium-induced calcium release in avian atrium. J Pharmacol Exp Ther 268 (3): 1476-84.
  5. Xu L, Tripathy A, Pasek D, Meissner G. Potential for pharmacology of ryanodine receptor/calcium release channels. Ann N Y Acad Sci 853: 130-48.
  6. Wang Y, Zheng Y, Mei Q, Wang Q, Collier M, Fleischer S, Xin H, Kotlikoff M (2004). FKBP12.6 and cADPR regulation of Ca2+ release in smooth muscle cells. Am J Physiol Cell Physiol 286 (3): C538-46.
  7. Tu J, Xiao B, Yuan J, Lanahan A, Leoffert K, Li M, Linden D, Worley P (1998). Homer binds a novel proline-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors. Neuron 21 (4): 717-26.

External linksEdit


fr:Récepteur de la ryanodine
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