Biology:Ryanodine receptor

From HandWiki

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ryanodine receptor 1 (skeletal)
Identifiers
SymbolRYR1
Alt. symbolsMHS, MHS1, CCO
NCBI gene6261
HGNC10483
OMIM180901
RefSeqNM_000540
UniProtP21817
Other data
LocusChr. 19 q13.1

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ryanodine receptor 2 (cardiac)
Identifiers
SymbolRYR2
NCBI gene6262
HGNC10484
OMIM180902
RefSeqNM_001035
UniProtQ92736
Other data
LocusChr. 1 q42.1-q43

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ryanodine receptor 3
Identifiers
SymbolRYR3
NCBI gene6263
HGNC10485
OMIM180903
RefSeqNM_001036
UniProtQ15413
Other data
LocusChr. 15 q14-q15

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Physiology

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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.[1] 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.[2]

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.[3] Calcium release from RyR has been shown to regulate ATP production in heart and pancreas cells.[4][5][6]

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).[1] 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.[7] 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).[8]

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 propagation 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.

Pharmacology

Ryanodine receptors are ligand-gated calcium channels, which are highly sensitive to modulation by endogenous ions, small molecules, pharmacological agents.[9] The receptors located along the sarcoplasmic reticulum, are responsible for storing calcium.[10] When calcium is triggered to released, via action potentials down the cell membrane, contractile proteins are activated, this is essential for excitation-contraction coupling of striated muscle.[9][10] Mutations in these proteins can cause RyR related myopathies ranging from mild to extreme including: muscle weakness, respiratory failure, cardiac arrest, sudden infant death syndrome (SIDS), exertional rhabdomyolysis (ER), central core disease (CCD), multiminicore disease (MmD), catecholaminergic polymorphic ventricular tachycardia (CPVT), and/or malignant hyperthermia (MH).[9] [11] Some of these disorders related to RyR mutations have high mortality rates so having pharmacological agents to treat these disorders or reverse these mutations would be a great step in future medicine.

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.

  • Activators:[12]
    • Direct Agonist: 4-chloro-m-cresol (4CmC)
      • Induces calcium release from ryanodine receptors and is used to investigate physiological and molecular functions in tissue, cells, and membranes.[13] 4CmC has also shown potential for being a diagnostic tool to recognize muscles that are susceptible to MH.[13]
      • It's proven to be a better activator compared to caffeine, only needing approximately 1 mM to induce the release of calcium vs caffeine's 5-10 mM concentration.[13]
      • RyR1 and RyR2 are most sensitive to 4CmC compared to the other isoforms.[13]
    • Direct Agonist: Suramin
      • Binds to the calmodulin (CaM) binding site on the ryanodine receptor which triggers calcium release from the SR.[14]
    • 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).[15]
  • Antagonists:[16]
    • Ryanodine
      • High concentration ryanodine (micromolar, > 10 ℳM), completely closes the RyR channels.[17]
      • Low concentration ryanodine (nanomolar, < 10 ℳM), locks the RyR channels at a half-open state.[17]
    • Dantrolene
      • Clinically used antagonist FDA approved to treat malignant hyperthermia (MH) and spasticity.[18]
      • Specifically targets RyR1 and RyR3.
    • Azumolene
      • Analog of Dantrolene, used to relax skeletal muscle by inhibiting the release of calcium from the SR.[19]
    • Ruthenium red
      • Experimental antagonist that binds to the channel pore and blocks RyR1 medicated calcium release.[20]
    • Procaine, tetracaine, etc. (local anesthetics)

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[21]

As Potential Drug Targets

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.[22]

Drug Target Effect Clinical Use Concerns
Tacrolimus (FK506), Rapamycin FKBP12/12.6-RyR Increases channel opening probability, enhances calcium release Immunosuppressant Disrupts channel stability and causes calcium leaks
Rycals: S107 and K201 (JTV519) FKBP12.6-RyR Stabilizes complex, prevents leak Heart Failure and catecholaminergic polymorphic ventricular tachycardia (CPVT) K201: Off-target SERCA inhibition
Dantrolene RyR1, RyR3 Skeletal Muscle Relaxant malignant hyperthermia (MH), spasticity No effect on RyR2
Doxorubicin, Tricyclic antidepressants RyR2, CASQ2 Reduces Ca²⁺ buffering Chemotherapy, antidepressants Cardiotoxicity
Flecainide Nav1.5 Channels, secondary effects on RyR2 Slows cardiac conduction velocity Atrial fibrillation, paroxysmal supraventricular tachycardias (PSVT), catecholaminergic polymorphic ventricular tachycardia (CPVT) Proarrhythmia
Statins HMG-CoA Reductase, RyR1 Abnormally opens RyR1 Hypercholesterolemia Adverse skeletal muscle effects, toxic calcium leakage

Associated proteins

RyRs form docking platforms for a multitude of proteins and small molecule ligands.[1] 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.[22]

The cardiac-specific isoform (RyR2) is known to form a quaternary complex with luminal calsequestrin, junctin, and triadin.[23] 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.[24]

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.[22]


Role in disease

RyR1 mutations are associated with malignant hyperthermia and central core disease.[25] 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.[26] 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.[27]

RyR2 mutations play a role in stress-induced polymorphic ventricular tachycardia (a form of cardiac arrhythmia) and ARVD.[28] 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,[29] and thus may play a role in the pathogenesis of neurodegenerative diseases, like Alzheimer's disease.[30]

The presence of antibodies against ryanodine receptors in blood serum has also been associated with myasthenia gravis (i.e., MG).[1] 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.[31]

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.[32] Normal (wild type) ryanodine receptors are involved in CICR in heart and other muscles, and RyR2 functions primarily in the myocardium (heart muscle).

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 Cite error: Invalid <ref> tag; no text was provided for refs named Marks2015
  2. ↑ "Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum". The American Journal of Physiology 245 (1): C1-14. July 1983. doi:10.1152/ajpcell.1983.245.1.C1. PMID 6346892. 
  3. ↑ "Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle". Science 262 (5134): 740–744. October 1993. doi:10.1126/science.8235594. PMID 8235594. Bibcode: 1993Sci...262..740C. 
  4. ↑ "Cardiomyocyte ATP production, metabolic flexibility, and survival require calcium flux through cardiac ryanodine receptors in vivo". The Journal of Biological Chemistry 288 (26): 18975–18986. June 2013. doi:10.1074/jbc.M112.427062. PMID 23678000. 
  5. ↑ "Glucagon-like peptide-1 mobilizes intracellular Ca2+ and stimulates mitochondrial ATP synthesis in pancreatic MIN6 beta-cells". The Biochemical Journal 369 (Pt 2): 287–299. January 2003. doi:10.1042/BJ20021288. PMID 12410638. 
  6. ↑ "Glucose and endoplasmic reticulum calcium channels regulate HIF-1beta via presenilin in pancreatic beta-cells". The Journal of Biological Chemistry 283 (15): 9909–9916. April 2008. doi:10.1074/jbc.M710601200. PMID 18174159. 
  7. ↑ "Kinetics of rapid Ca2+ release by sarcoplasmic reticulum. Effects of Ca2+, Mg2+, and adenine nucleotides". Biochemistry 25 (1): 236–244. January 1986. doi:10.1021/bi00349a033. PMID 3754147. 
  8. ↑ "Ryanodine receptors: structure and function". The Journal of Biological Chemistry 287 (38): 31624–31632. September 2012. doi:10.1074/jbc.r112.349068. PMID 22822064. 
  9. ↑ 9.0 9.1 9.2 "Physiology and Pharmacology of Ryanodine Receptor Calcium Release Channels" (in en-US), Ion Channels DownUnder, Advances in Pharmacology, 79, Academic Press, 2017-01-01, pp. 287–324, doi:10.1016/bs.apha.2016.12.001, ISBN 978-0-12-810413-2, PMID 28528672, https://www.sciencedirect.com/science/chapter/bookseries/abs/pii/S1054358916300680, retrieved 2026-04-09 
  10. ↑ 10.0 10.1 Wang, Kai; Tu, Yuhai; Rappel, Wouter-Jan; Levine, Herbert (November 2005). "Excitation-contraction coupling gain and cooperativity of the cardiac ryanodine receptor: a modeling approach". Biophysical Journal 89 (5): 3017–3025. doi:10.1529/biophysj.105.058958. ISSN 0006-3495. PMID 16126827. Bibcode: 2005BpJ....89.3017W. 
  11. ↑ Wang, Fenglin; Yu, Jingbo; Lin, Ping; Sigalas, Charalampos; Zhang, Shibo; Gong, Yuan; Sitsapesan, Rebecca; Song, Lele (2022-09-27). "The ryanodine receptor mutational characteristics and its indication for cancer prognosis". Scientific Reports 12 (1): 16113. doi:10.1038/s41598-022-19905-y. ISSN 2045-2322. PMID 36167878. Bibcode: 2022NatSR..1216113W. 
  12. ↑ "Potential for pharmacology of ryanodine receptor/calcium release channels". Annals of the New York Academy of Sciences 853 (1): 130–148. September 1998. doi:10.1111/j.1749-6632.1998.tb08262.x. PMID 10603942. Bibcode: 1998NYASA.853..130T. 
  13. ↑ 13.0 13.1 13.2 13.3 Al-Mousa, Fawaz; Michelangeli, Francesco (2009). "Commonly used ryanodine receptor activator, 4-chloro-m-cresol (4CmC), is also an inhibitor of SERCA Ca2+ pumps". Pharmacological Reports: PR 61 (5): 838–842. doi:10.1016/s1734-1140(09)70139-2. ISSN 2299-5684. PMID 19904006. 
  14. ↑ Klinger, Markus; Freissmuth, Michael; Nickel, Peter; Stäbler-Schwarzbart, Margit; Kassack, Matthias; Suko, Josef; Hohenegger, Martin (1999-03-01). "Suramin and Suramin Analogs Activate Skeletal Muscle Ryanodine Receptor via a Calmodulin Binding Site". Molecular Pharmacology 55 (3): 462–472. doi:10.1016/S0026-895X(24)12170-0. ISSN 0026-895X. PMID 10051529. https://www.sciencedirect.com/science/article/pii/S0026895X24121700. 
  15. ↑ "FKBP12.6 and cADPR regulation of Ca2+ release in smooth muscle cells". American Journal of Physiology. Cell Physiology 286 (3): C538–C546. March 2004. doi:10.1152/ajpcell.00106.2003. PMID 14592808. 
  16. ↑ "Distinct modes of inhibition by ruthenium red and ryanodine of calcium-induced calcium release in avian atrium". The Journal of Pharmacology and Experimental Therapeutics 268 (3): 1476–1484. March 1994. doi:10.1016/S0022-3565(25)38589-7. PMID 7511166. 
  17. ↑ 17.0 17.1 "Ryanodine Receptor Projects" (in en). https://medicine.yale.edu/lab/ehrlich/projects/intracellular/ryanodine/. 
  18. ↑ Inan, Saadet; Wei, Huafeng (December 2010). "The cytoprotective effects of dantrolene: a ryanodine receptor antagonist". Anesthesia and Analgesia 111 (6): 1400–1410. doi:10.1213/ANE.0b013e3181f7181c. ISSN 1526-7598. PMID 20861418. 
  19. ↑ Zhao, Xiaoli; Weisleder, Noah; Han, Xuehai; Pan, Zui; Parness, Jerome; Brotto, Marco; Ma, Jianjie (2006-11-03). "Azumolene inhibits a component of store-operated calcium entry coupled to the skeletal muscle ryanodine receptor". The Journal of Biological Chemistry 281 (44): 33477–33486. doi:10.1074/jbc.M602306200. ISSN 0021-9258. PMID 16945924. Bibcode: 2006JBiCh.28133477Z. 
  20. ↑ Jain, Swati; Sharma, Bhupesh (2016-10-01). "Effect of ruthenium red, a ryanodine receptor antagonist in experimental diabetes induced vascular endothelial dysfunction and associated dementia in rats". Physiology & Behavior 164 (Pt A): 140–150. doi:10.1016/j.physbeh.2016.05.052. ISSN 1873-507X. PMID 27262216. 
  21. ↑ "Homer binds a novel proline-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors". Neuron 21 (4): 717–726. October 1998. doi:10.1016/S0896-6273(00)80589-9. PMID 9808459. 
  22. ↑ 22.0 22.1 22.2 Cite error: Invalid <ref> tag; no text was provided for refs named :0
  23. ↑ "Calsequestrin interacts directly with the cardiac ryanodine receptor luminal domain". Journal of Cell Science 129 (21): 3983–3988. November 2016. doi:10.1242/jcs.191643. PMID 27609834. 
  24. ↑ Meissner, Gerhard (2002-11-01). "Regulation of mammalian ryanodine receptors". Frontiers in Bioscience: A Journal and Virtual Library 7 (4): d2072–2080. doi:10.2741/A899. ISSN 1093-9946. PMID 12438018. 
  25. ↑ "RYR1 mutations causing central core disease are associated with more severe malignant hyperthermia in vitro contracture test phenotypes". Human Mutation 20 (2): 88–97. August 2002. doi:10.1002/humu.10098. PMID 12124989. 
  26. ↑ "Functional defects in six ryanodine receptor isoform-1 (RyR1) mutations associated with malignant hyperthermia and their impact on skeletal excitation-contraction coupling". The Journal of Biological Chemistry 278 (28): 25722–25730. July 2003. doi:10.1074/jbc.m302165200. PMID 12732639. 
  27. ↑ "Thermogenesis and energy expenditure: control of heat production by the Ca(2+)-ATPase of fast and slow muscle". Molecular Membrane Biology 19 (4): 301–310. 2002-01-01. doi:10.1080/09687680210166217. PMID 12512777. 
  28. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Zucchi
  29. ↑ "Presenilin-1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons". The Journal of Biological Chemistry 275 (24): 18195–18200. June 2000. doi:10.1074/jbc.M000040200. PMID 10764737. 
  30. ↑ "Polymorphisms Within RYR3 Gene Are Associated With Risk and Age at Onset of Hypertension, Diabetes, and Alzheimer's Disease". American Journal of Hypertension 31 (7): 818–826. June 2018. doi:10.1093/ajh/hpy046. PMID 29590321. 
  31. ↑ "Myasthenia gravis, respiratory function, and respiratory tract disease". Journal of Neurology 270 (7): 3329–3340. July 2023. doi:10.1007/s00415-023-11733-y. PMID 37101094. 
  32. ↑ "Identification of a Novel Homozygous Multi-Exon Duplication in RYR2 Among Children With Exertion-Related Unexplained Sudden Deaths in the Amish Community". JAMA Cardiology 5 (3): 13–18. March 2020. doi:10.1001/jamacardio.2019.5400. PMID 31913406. 
  33. ↑ Sparks, Thomas C (2024). "Insecticide mixtures—uses, benefits and considerations". Pest Management Science 81 (3): 1137–1144. doi:10.1002/ps.7980. PMID 38356314. 
  34. ↑ Nauen, Ralf; Steinbach, Denise (27 August 2016). "Resistance to Diamide Insecticides in Lepidopteran Pests". in Horowitz, A. Rami. Advances in Insect Control and Resistance Management. Cham: Springer. 26 August 2016. pp. 219–240. doi:10.1007/978-3-319-31800-4_12. ISBN 978-3-319-31800-4. https://doi.org/10.1007/978-3-319-31800-4_12. 



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