ryanodine receptor

Ryanodine receptors are multidomain homotetramers which regulate intracellular calcium ion release from the sarcoplasmic and endoplasmic reticula.{{cite book |title=Membrane Protein Complexes: Structure and Function |vauthors=Santulli G, Lewis D, des Georges A, Marks AR, Frank J |date=2018 |journal=Sub-Cellular Biochemistry |publisher=Springer Singapore |isbn=978-981-10-7756-2 |veditors=Harris JR, Boekema EJ |volume=87 |place=Singapore |pages=329–352 |chapter=Ryanodine Receptor Structure and Function in Health and Disease |doi=10.1007/978-981-10-7757-9_11 |pmc=5936639 |pmid=29464565}} They are the largest known ion channels, with weights exceeding 2 megadaltons, and their structural complexity enables a wide variety of allosteric regulation mechanisms.{{cite journal |vauthors=Lanner JT, Georgiou DK, Joshi AD, Hamilton SL |date=November 2010 |title=Ryanodine receptors: structure, expression, molecular details, and function in calcium release |journal=Cold Spring Harbor Perspectives in Biology |volume=2 |issue=11 |pages=a003996 |doi=10.1101/cshperspect.a003996 |pmc=2964179 |pmid=20961976}}{{cite journal |vauthors=Van Petegem F |date=January 2015 |title=Ryanodine receptors: allosteric ion channel giants |journal=Journal of Molecular Biology |volume=427 |issue=1 |pages=31–53 |doi=10.1016/j.jmb.2014.08.004 |pmid=25134758}}

RyR1 cryo-EM structure revealed a large cytosolic assembly built on an extended α-solenoid scaffold connecting key regulatory domains to the pore. The RyR1 pore architecture shares the general structure of the six-transmembrane ion channel superfamily. A unique domain inserted between the second and third transmembrane helices interacts intimately with paired EF-hands originating from the α-solenoid scaffold, suggesting a mechanism for channel gating by Ca²⁺.{{cite journal |display-authors=6 |vauthors=Zalk R, Clarke OB, des Georges A, Grassucci RA, Reiken S, Mancia F, Hendrickson WA, Frank J, Marks AR |date=January 2015 |title=Structure of a mammalian ryanodine receptor |journal=Nature |volume=517 |issue=7532 |pages=44–49 |bibcode=2015Natur.517...44Z |doi=10.1038/nature13950 |pmc=4300236 |pmid=25470061}}

The ryanodine receptors are named after the plant alkaloid ryanodine which shows a high affinity to them.

There are multiple isoforms of ryanodine receptors:

• RyR1 is primarily expressed in skeletal muscle
• It is essential for excitation-contraction coupling
• RyR2 is primarily expressed in myocardium (heart muscle)
• the major cellular mediator of calcium-induced calcium release (CICR) in animal cells.

• RyR3 is expressed more widely, but especially in the brain.{{cite journal | vauthors = Zucchi R, Ronca-Testoni S | title = The sarcoplasmic reticulum Ca2+ channel/ryanodine receptor: modulation by endogenous effectors, drugs and disease states | journal = Pharmacological Reviews | volume = 49 | issue = 1 | pages = 1–51 | date = March 1997 | doi = 10.1016/S0031-6997(24)01312-7 | pmid = 9085308 }}
• It is involved in neuroprotection, memory, pain modulation, and social behavior.{{Cite journal |last=Mackrill |first=John J. |date=2010-06-01 |title=Ryanodine receptor calcium channels and their partners as drug targets |url=https://www.sciencedirect.com/science/article/abs/pii/S0006295210000250 |journal=Biochemical Pharmacology |volume=79 |issue=11 |pages=1535–1543 |doi=10.1016/j.bcp.2010.01.014 |issn=0006-2952}}

Non-mammalian vertebrates typically express two RyR isoforms, referred to as RyR-alpha and RyR-beta. Many invertebrates, including the model organisms Drosophila melanogaster (fruitfly) and Caenorhabditis elegans, only have a single isoform. In non-metazoan species, calcium-release channels with sequence homology to RyRs can be found, but they are shorter than the mammalian ones and may be closer to inositol trisphosphate (IP₃) receptors.

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Ryanodine receptors mediate the release of calcium ions from the sarcoplasmic reticulum and endoplasmic reticulum, an essential step in muscle contraction. In skeletal muscle, activation of ryanodine receptors occurs via a physical coupling to the dihydropyridine receptor (a voltage-dependent, L-type calcium channel), whereas in cardiac muscle, the primary mechanism of activation is calcium-induced calcium release, which causes calcium outflow from the sarcoplasmic reticulum.{{cite journal | vauthors = Fabiato A | title = Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum | journal = The American Journal of Physiology | volume = 245 | issue = 1 | pages = C1-14 | date = July 1983 | pmid = 6346892 | doi = 10.1152/ajpcell.1983.245.1.C1 }}

It has been shown that calcium release from a number of ryanodine receptors in a RyR cluster results in a spatiotemporally-restricted rise in cytosolic calcium that can be visualized as a calcium spark.{{cite journal | vauthors = 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 | date = October 1993 | pmid = 8235594 | doi = 10.1126/science.8235594 | bibcode = 1993Sci...262..740C }} Calcium release from RyR has been shown to regulate ATP production in heart and pancreas cells.{{cite journal | vauthors = Bround MJ, Wambolt R, Luciani DS, Kulpa JE, Rodrigues B, Brownsey RW, Allard MF, Johnson JD | display-authors = 6 | title = Cardiomyocyte ATP production, metabolic flexibility, and survival require calcium flux through cardiac ryanodine receptors in vivo | journal = The Journal of Biological Chemistry | volume = 288 | issue = 26 | pages = 18975–18986 | date = June 2013 | pmid = 23678000 | pmc = 3696672 | doi = 10.1074/jbc.M112.427062 | doi-access = free }}{{cite journal | vauthors = Tsuboi T, da Silva Xavier G, Holz GG, Jouaville LS, Thomas AP, Rutter GA | title = Glucagon-like peptide-1 mobilizes intracellular Ca2+ and stimulates mitochondrial ATP synthesis in pancreatic MIN6 beta-cells | journal = The Biochemical Journal | volume = 369 | issue = Pt 2 | pages = 287–299 | date = January 2003 | pmid = 12410638 | pmc = 1223096 | doi = 10.1042/BJ20021288 }}{{cite journal | vauthors = Dror V, Kalynyak TB, Bychkivska Y, Frey MH, Tee M, Jeffrey KD, Nguyen V, Luciani DS, Johnson JD | display-authors = 6 | title = Glucose and endoplasmic reticulum calcium channels regulate HIF-1beta via presenilin in pancreatic beta-cells | journal = The Journal of Biological Chemistry | volume = 283 | issue = 15 | pages = 9909–9916 | date = April 2008 | pmid = 18174159 | doi = 10.1074/jbc.M710601200 | doi-access = free }}

Ryanodine receptors are similar to the inositol trisphosphate (IP₃ or InsP₃) 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). However, as the concentration of intracellular Ca²⁺ rises, this can trigger closing of RyR, preventing the total depletion of SR. This finding indicates that a plot of opening probability for RyR as a function of Ca²⁺ concentration is a bell-curve.{{cite journal | vauthors = Meissner G, Darling E, Eveleth J | title = Kinetics of rapid Ca2+ release by sarcoplasmic reticulum. Effects of Ca2+, Mg2+, and adenine nucleotides | journal = Biochemistry | volume = 25 | issue = 1 | pages = 236–244 | date = January 1986 | pmid = 3754147 | doi = 10.1021/bi00349a033 }} Furthermore, RyR can sense the Ca²⁺ concentration inside the ER/SR and spontaneously open in a process known as store overload-induced calcium release (SOICR).{{cite journal | vauthors = Van Petegem F | title = Ryanodine receptors: structure and function | journal = The Journal of Biological Chemistry | volume = 287 | issue = 38 | pages = 31624–31632 | date = September 2012 | pmid = 22822064 | pmc = 3442496 | doi = 10.1074/jbc.r112.349068 | doi-access = free }}

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 propogation of the wave is accomplished by the feedback mechanism of the ryanodine receptor. The activation of phospholipase C by GPCR or RTK triggers the production of inositol trisphosphate, which activates of the InsP₃ receptor.

• Antagonists:{{cite journal | vauthors = Vites AM, Pappano AJ | title = Distinct modes of inhibition by ruthenium red and ryanodine of calcium-induced calcium release in avian atrium | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 268 | issue = 3 | pages = 1476–1484 | date = March 1994 | doi = 10.1016/S0022-3565(25)38589-7 | pmid = 7511166 }}
• 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:{{cite journal | vauthors = Xu L, Tripathy A, Pasek DA, Meissner G | title = Potential for pharmacology of ryanodine receptor/calcium release channels | journal = Annals of the New York Academy of Sciences | volume = 853 | issue = 1 | pages = 130–148 | date = September 1998 | pmid = 10603942 | doi = 10.1111/j.1749-6632.1998.tb08262.x | s2cid = 86436194 | bibcode = 1998NYASA.853..130T }}
• 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 12 kDa 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).{{cite journal | vauthors = Wang YX, Zheng YM, Mei QB, Wang QS, Collier ML, Fleischer S, Xin HB, Kotlikoff MI | display-authors = 6 | title = FKBP12.6 and cADPR regulation of Ca2+ release in smooth muscle cells | journal = American Journal of Physiology. Cell Physiology | volume = 286 | issue = 3 | pages = C538–C546 | date = March 2004 | pmid = 14592808 | doi = 10.1152/ajpcell.00106.2003 | s2cid = 20900277 }}

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 stores with cell surface group 1 metabotropic glutamate receptors and the Alpha-1D adrenergic receptor{{cite journal | vauthors = Tu JC, Xiao B, Yuan JP, Lanahan AA, Leoffert K, Li M, Linden DJ, Worley PF | display-authors = 6 | 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 = 717–726 | date = October 1998 | pmid = 9808459 | doi = 10.1016/S0896-6273(00)80589-9 | s2cid = 2851554 | doi-access = free }}

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.

The diamides, an important class of insecticide making up 13% of the insecticide market,{{Cite journal |last=Sparks |first=Thomas C |date=2024 |title=Insecticide mixtures—uses, benefits and considerations |url=https://doi.org/10.1002/ps.7980 |journal=Pest Management Science |volume=81 |issue=3 |pages=1137–1144 |doi=10.1002/ps.7980 |pmid=38356314 |via=Wiley}} work by activating insect RyRs.{{Cite book |last1=Nauen |first1=Ralf |title=Advances in Insect Control and Resistance Management |last2=Steinbach |first2=Denise |date=27 August 2016 |publisher=Springer |year=2016 |isbn=978-3-319-31800-4 |editor-last=Horowitz |editor-first=A. Rami |location=Cham |publication-date=26 August 2016 |pages=219–240 |chapter=Resistance to Diamide Insecticides in Lepidopteran Pests |doi=10.1007/978-3-319-31800-4_12 |editor-last2=Ishaaya |editor-first2=Isaac |chapter-url=https://doi.org/10.1007/978-3-319-31800-4_12}}

RyRs form docking platforms for a multitude of proteins and small molecule ligands. Accessory proteins bind these channels and regulate their gating, localization, expression, and integration with cellular signaling in a tissue- and isoform-specific manner.

FK506-Binding Proteins (FKBP12 / FKBP12.6) — aka Calstabin-1 and Calstabin-2 — stabilize the closed state of RyRs, preventing pathological Ca²⁺ leak.

The cardiac-specific isoform (RyR2) is known to form a quaternary complex with luminal calsequestrin, junctin, and triadin.{{cite journal |vauthors=Handhle A, Ormonde CE, Thomas NL, Bralesford C, Williams AJ, Lai FA, Zissimopoulos S |date=November 2016 |title=Calsequestrin interacts directly with the cardiac ryanodine receptor luminal domain |journal=Journal of Cell Science |volume=129 |issue=21 |pages=3983–3988 |doi=10.1242/jcs.191643 |pmc=5117208 |pmid=27609834}} Calsequestrin (CASQ) has multiple Ca²⁺ binding sites that bind with very low affinity, allowing easy ion release. It acts as RyR gate modulators by signaling when Ca²⁺ stores are full. Triadin and Junctin are sarcoplasmic reticulum (SR) membrane proteins that link RyRs to CASQ and also respond to Ca²⁺ store levels.{{Cite journal |last=Meissner |first=Gerhard |date=2002-11-01 |title=Regulation of mammalian ryanodine receptors |url=https://pubmed.ncbi.nlm.nih.gov/12438018 |journal=Frontiers in Bioscience: A Journal and Virtual Library |volume=7 |issue=4 |pages=d2072–2080 |doi=10.2741/A899 |issn=1093-9946 |pmid=12438018}}

Calmodulin (CaM) and S100A1 both bind the same site on RyRs (especially RyR1 and RyR2), but exert opposite effects: Ca²⁺-bound CaM inhibits RyRs while S100A1 enhances its opening. Expression levels and competition between these proteins tune RyR responses to Ca²⁺ signals.

RyR1 mutations are associated with malignant hyperthermia and central core disease.{{cite journal | vauthors = Robinson RL, Brooks C, Brown SL, Ellis FR, Halsall PJ, Quinnell RJ, Shaw MA, Hopkins PM | display-authors = 6 | title = RYR1 mutations causing central core disease are associated with more severe malignant hyperthermia in vitro contracture test phenotypes | journal = Human Mutation | volume = 20 | issue = 2 | pages = 88–97 | date = August 2002 | pmid = 12124989 | doi = 10.1002/humu.10098 | s2cid = 21497303 | doi-access = free }} Mutant-type RyR1 receptors exposed to volatile anesthetics or other triggering agents can display an increased affinity for cytoplasmic Ca²⁺ at activating sites as well as a decreased cytoplasmic Ca²⁺ affinity at inhibitory sites.{{cite journal | vauthors = Yang T, Ta TA, Pessah IN, Allen PD | title = Functional defects in six ryanodine receptor isoform-1 (RyR1) mutations associated with malignant hyperthermia and their impact on skeletal excitation-contraction coupling | journal = The Journal of Biological Chemistry | volume = 278 | issue = 28 | pages = 25722–25730 | date = July 2003 | pmid = 12732639 | doi = 10.1074/jbc.m302165200 | doi-access = free}} The breakdown of this feedback mechanism causes uncontrolled release of Ca²⁺ into the cytoplasm, and increased ATP hydrolysis resulting from ATPase enzymes shuttling Ca²⁺ back into the sarcoplasmic reticulum leads to excessive heat generation.{{cite journal | vauthors = Reis M, Farage M, de Meis L | title = Thermogenesis and energy expenditure: control of heat production by the Ca(2+)-ATPase of fast and slow muscle | journal = Molecular Membrane Biology | volume = 19 | issue = 4 | pages = 301–310 | date = 2002-01-01 | pmid = 12512777 | doi = 10.1080/09687680210166217 | s2cid = 10720335 | doi-access = free }}

RyR2 mutations play a role in stress-induced polymorphic ventricular tachycardia (a form of cardiac arrhythmia) and ARVD. 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,{{cite journal | vauthors = Chan SL, Mayne M, Holden CP, Geiger JD, Mattson MP | title = Presenilin-1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons | journal = The Journal of Biological Chemistry | volume = 275 | issue = 24 | pages = 18195–18200 | date = June 2000 | pmid = 10764737 | doi = 10.1074/jbc.M000040200 | doi-access = free }} and thus may play a role in the pathogenesis of neurodegenerative diseases, like Alzheimer's disease.{{cite journal | vauthors = Gong S, Su BB, Tovar H, Mao C, Gonzalez V, Liu Y, Lu Y, Wang KS, Xu C | display-authors = 6 | title = Polymorphisms Within RYR3 Gene Are Associated With Risk and Age at Onset of Hypertension, Diabetes, and Alzheimer's Disease | journal = American Journal of Hypertension | volume = 31 | issue = 7 | pages = 818–826 | date = June 2018 | pmid = 29590321 | doi = 10.1093/ajh/hpy046 | doi-access = free }}

The presence of antibodies against ryanodine receptors in blood serum has also been associated with myasthenia gravis (i.e., MG). Individuals with MG who have antibodies directed against ryanodine receptors typically have a more severe form of generalized MG in which their skeletal muscle weaknesses involve muscles that govern basic life functions.{{cite journal | vauthors = Gilhus NE | title = Myasthenia gravis, respiratory function, and respiratory tract disease | journal = Journal of Neurology | volume = 270 | issue = 7 | pages = 3329–3340 | date = July 2023 | pmid = 37101094 | pmc = 10132430 | doi = 10.1007/s00415-023-11733-y | url = }}

Sudden cardiac death in several young individuals in the Amish community (four of which were from the same family) was traced to homozygous duplication of a mutant RyR2 (Ryanodine Receptor) gene.{{cite journal | vauthors = Tester DJ, Bombei HM, Fitzgerald KK, Giudicessi JR, Pitel BA, Thorland EC, Russell BG, Hamrick SK, Kim CS, Haglund-Turnquist CM, Johnsrude CL, Atkins DL, Ochoa Nunez LA, Law I, Temple J, Ackerman MJ | display-authors = 6 | title = Identification of a Novel Homozygous Multi-Exon Duplication in RYR2 Among Children With Exertion-Related Unexplained Sudden Deaths in the Amish Community | journal = JAMA Cardiology | volume = 5 | issue = 3 | pages = 13–18 | date = March 2020 | pmid = 31913406 | pmc = 6990654 | doi = 10.1001/jamacardio.2019.5400 }} Normal (wild type) ryanodine receptors are involved in CICR in heart and other muscles, and RyR2 functions primarily in the myocardium (heart muscle).

The expression, distribution, and gating of RyRs are modified by cellular proteins, presenting an opportunity to develop new drugs that target RyR channel complexes by manipulating these proteins. Several drugs, such as FK506, rapamycin, and K201, can modify interactions between RyRs and their accessory proteins.

• Diamide, a class of insecticide that act through ryanodine receptors
• Neuromuscular junction
• Dihydropyridine receptor

{{Reflist|32em}}

• {{MeshName|Ryanodine+Receptor}}

{{Ion channels|g1}}

{{Calcium signaling}}

Category:Transmembrane receptors

Category:Calcium channels