Ryanodine receptor
1863128
221169543
2008-06-23T10:01:08Z
DOI bot
6652755
Citation maintenance. You can [[WP:DOI|use this bot]] yourself! Please [[User:DOI_bot/bugs|report any bugs]].
{{protein
| Name = [[RYR1|ryanodine receptor 1 (skeletal)]]
| caption =
| image =
| width =
| HGNCid = 10483
| Symbol = [[RYR1]]
| AltSymbols = MHS, MHS1, CCO
| EntrezGene = 6261
| OMIM = 180901
| RefSeq = NM_000540
| UniProt = P21817
| PDB =
| ECnumber =
| Chromosome = 19
| Arm = q
| Band = 13.1
| LocusSupplementaryData =
}}
{{protein
| Name = [[RYR2|ryanodine receptor 2 (cardiac)]]
| caption =
| image =
| width =
| HGNCid = 10484
| Symbol = [[RYR2]]
| AltSymbols =
| EntrezGene = 6262
| OMIM = 180902
| RefSeq = NM_001035
| UniProt = Q92736
| PDB =
| ECnumber =
| Chromosome = 1
| Arm = q
| Band = 42.1
| LocusSupplementaryData = -q43
}}
{{protein
| Name = [[RYR3|ryanodine receptor 3]]
| caption =
| image =
| width =
| HGNCid = 10485
| Symbol = [[RYR3]]
| AltSymbols =
| EntrezGene = 6263
| OMIM = 180903
| RefSeq = NM_001036
| UniProt = Q15413
| PDB =
| ECnumber =
| Chromosome = 15
| Arm = q
| Band = 14
| LocusSupplementaryData = -q15
}}
'''Ryanodine receptors''' ('''RyRs''') form a class of intracellular [[calcium channel]]s in various forms of excitable animal [[tissue (biology)|tissue]] like [[muscle]]s and [[neuron]]s. It is the major cellular mediator of '''[[calcium-induced calcium release]]''' (CICR) in animal [[cell (biology)|cell]]s.
==Etymology==
The receptors are named after the [[plant]] [[alkaloid]] [[ryanodine]], to which they show high affinity:
<gallery>
Image:Ryanodin.svg|[[Ryanodine]]
</gallery>
==Isoforms==
There are multiple isoforms of ryanodine [[receptor (biochemistry)|receptor]]s:
* RyR1 is primarily expressed in [[skeletal muscle]]
* RyR2 in [[myocardium]] (heart muscle)
* A third form, RyR3, is expressed more widely, but especially in the [[brain]]<ref name=Zucchi>Zucchi R, Ronca-Testoni S. The sarcoplasmic reticulum Ca<sup>2+</sup> channel/ryanodine receptor: modulation by endogenous effectors, drugs, and disease states. ''Pharmacol Rev'' 1997;49:1-51. PMID 9085308.</ref>.
* There is also a fourth form found only in fish.
==Physiology==
Ryanodine receptors mediate the release of [[calcium in biology|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]], whereas, in [[cardiac muscle]], the primary mechanism is [[calcium-induced calcium release]] <ref>{{cite journal |author=Fabiato A |title=Calcium-induced calcium release of calcium from the cardiac sarcoplasmic reticulum |journal=Am J Physiol |volume=245 |issue=1 |pages=C1–C14 |year=1983 |pmid=6346892}}</ref>.
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'' <ref>{{cite journal |author=Cheng H, Lederer WJ, Cannell MB |title=Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle |journal=Science |volume=262 |issue=5134 |pages=740–744 |year=1993 |pmid=8235594 |doi=10.1126/science.8235594}}</ref>.
Ryanodine receptors are similar to the inositol triphosphate (IP<sub><small>3</small></sub>) receptor, and stimulated to transport Ca<small><sup>2+</sup></small> into the cytosol by recognizing Ca<small><sup>2+</sup></small> on its ''cytosolic side'', thus establishing a [[positive feedback]] mechanism; a small amount of Ca<small><sup>2+</sup></small> in the cytosol near the receptor will cause it to release even more Ca<small><sup>2+</sup></small> (calcium-induced calcium release/CICR).<ref name=Zucchi/>
RyRs are especially important in [[neuron]]s and [[muscle cell]]s. In [[heart]] and [[pancreas]] cells, another second messenger ([[cyclic ADP-ribose]]) takes part in the receptor activation.
The localized and time-limited activity of Ca<small><sup>2+</sup></small> in the cytosol is also called a ''Ca<small><sup>2+</sup></small> wave''. The building of the wave is done by
* the feedback mechanism of the ryanodine receptor
* the activation of [[phospholipase C]] by [[GPCR]] or TRK, which leads to the production of [[inositol triphosphate]], which in turn activates the InsP<sub><small>3</small></sub> receptor. <!-- This paragraph is not very clear. -->
===Pharmacology===
*'''Antagonists''':<ref>{{cite journal |author=Vites A, Pappano A |title=Distinct modes of inhibition by ruthenium red and ryanodine of calcium-induced calcium release in avian atrium |journal=J Pharmacol Exp Ther |volume=268 |issue=3 |pages=1476–84 |year=1994 |pmid=7511166}}</ref>
**[[Ryanodine]] locks the RyRs at half-open state at nanomolar concentrations, yet fully closes them at micromolar concentration.
**[[Dantrolene]] the clinically-used antagonist
**[[Ruthenium red]]
**[[procaine]], [[tetracaine]], etc. (local anesthetics)
*'''Activators''':<ref>{{cite journal |author=Xu L, Tripathy A, Pasek D, Meissner G |title=Potential for pharmacology of ryanodine receptor/calcium release channels |journal=Ann N Y Acad Sci |volume=853 |issue= |pages=130–48 |year= |pmid=10603942 |doi=10.1111/j.1749-6632.1998.tb08262.x}}</ref>
**Agonist: [[4-chloro-m-cresol]] and [[suramin]] are direct agonists, i.e., direct activators.
**Xanthines like [[caffeine]] and [[pentifylline]] activate it by potentiating sensitivity to native ligand Ca.
*** Physiological agonist: [[Cyclic ADP-ribose]] 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).<ref>{{cite journal |author=Wang Y, Zheng Y, Mei Q, Wang Q, Collier M, Fleischer S, Xin H, Kotlikoff M |title=FKBP12.6 and cADPR regulation of Ca2+ release in smooth muscle cells |journal=Am J Physiol Cell Physiol |volume=286 |issue=3 |pages=C538–46 |year=2004 |pmid=14592808 |doi=10.1152/ajpcell.00106.2003}}</ref>
A variety of other molecules may interact with and regulate Ryanodine receptor. For example: Dimerized [[Homer (protein)|Homer]] physical tether linking inositol trisphosphate receptors (IP3R) and ryanodine receptors on the intracellular calcium stores with cell surface group 1 metabotropic Glutamate Receptors and the alpha 1D adrenergic receptor<ref>{{cite journal |author=Tu J, Xiao B, Yuan J, Lanahan A, Leoffert K, Li M, Linden D, Worley P |title=Homer binds a novel proline-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors |journal=Neuron |volume=21 |issue=4 |pages=717–26 |year=1998 |pmid=9808459 |doi=10.1016/S0896-6273(00)80589-9}}</ref>
====Ryanodine====
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 Micro[[Mole (unit)|Molar]], 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.
====Caffeine====
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 Ca<sup>2+</sup> in the presence of caffeine, such that basal Ca<sup>2+</sup> 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 disease==
RyR1 [[mutation]]s are associated with [[malignant hyperthermia]] and [[central core disease]]. RyR2 mutations play a role in stress-induced [[Polymorphism (biology)|polymorphic]] [[ventricular tachycardia]] (a form of [[cardiac arrhythmia]]) and [[Arrhythmogenic right ventricular dysplasia|ARVD]].<ref name=Zucchi/> 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 [[neurodegeneration|neurodegenerative]] diseases, like [[Alzheimer's disease]].
The presence of [[antibody|antibodies]] against ryanodine receptors in [[blood serum]] has also been associated with [[myasthenia gravis]].
==References==
{{Reflist|2}}
==External links==
* {{MeshName|Ryanodine+Receptor}}
{{Ion channels}}
[[Category:Transmembrane receptors]]
[[de:Ryanodin-Rezeptor]]
[[fr:Récepteur de la ryanodine]]