Biology:Ryanodine receptor 2

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Short description: Transport protein and coding gene in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Ryanodine receptor 2 (RYR2) is one of a class of ryanodine receptors and a protein found primarily in cardiac muscle. In humans, it is encoded by the RYR2 gene.[1][2][3] In the process of cardiac calcium-induced calcium release, RYR2 is the major mediator for sarcoplasmic release of stored calcium ions.

Structure

The channel is composed of RYR2 homotetramers and FK506-binding proteins found in a 1:4 stoichiometric ratio. Calcium channel function is affected by the specific type of FK506 isomer interacting with the RYR2 protein, due to binding differences and other factors.[4]

Function

The RYR2 protein functions as the major component of a calcium channel located in the sarcoplasmic reticulum that supplies ions to the cardiac muscle during systole. To enable cardiac muscle contraction, calcium influx through voltage-gated L-type calcium channels in the plasma membrane allows calcium ions to bind to RYR2 located on the sarcoplasmic reticulum. This binding causes the release of calcium through RYR2 from the sarcoplasmic reticulum into the cytosol, where it binds to the C domain of troponin, which shifts tropomyosin and allows the myosin ATPase to bind to actin, enabling cardiac muscle contraction.[5] RYR2 channels are associated with many cellular functions, including mitochondrial metabolism, gene expression and cell survival, in addition to their role in cardiomyocyte contraction.[6]

Clinical significance

Deleterious mutations of the ryanodine receptor family, and especially the RYR2 receptor, lead to a constellation of pathologies leading to both acute and chronic heart failure collectively known as "Ryanopathies."[7]

Mutations in the RYR2 gene are associated with catecholaminergic polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia.[8]

Recently, 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 gene.[9] Normal (wild type) RyR2 functions primarily in the myocardium (heart muscle).

Mice with genetically reduced RYR2 exhibit a lower basal heart rate and fatal arrhythmias.[10]

Interactions

Ryanodine receptor 2 has been shown to interact with:

See also

References

  1. ↑ "Molecular cloning of cDNA encoding the Ca2+ release channel (ryanodine receptor) of rabbit cardiac muscle sarcoplasmic reticulum". The Journal of Biological Chemistry 265 (23): 13472–83. August 1990. doi:10.1016/S0021-9258(18)77371-7. PMID 2380170. 
  2. ↑ "Chromosome mapping of five human cardiac and skeletal muscle sarcoplasmic reticulum protein genes". Genomics 17 (2): 507–9. August 1993. doi:10.1006/geno.1993.1357. PMID 8406504. 
  3. ↑ "Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2)". Human Molecular Genetics 10 (3): 189–94. February 2001. doi:10.1093/hmg/10.3.189. PMID 11159936. 
  4. ↑ "Kinetics of FKBP12.6 binding to ryanodine receptors in permeabilized cardiac myocytes and effects on Ca sparks". Circulation Research 106 (11): 1743–52. June 2010. doi:10.1161/CIRCRESAHA.110.219816. PMID 20431056. 
  5. ↑ "Q92736 - RYR2_HUMAN". https://www.uniprot.org/uniprot/Q92736. 
  6. ↑ "Cardiomyocyte ATP production, metabolic flexibility, and survival require calcium flux through cardiac ryanodine receptors in vivo". The Journal of Biological Chemistry 288 (26): 18975–86. June 2013. doi:10.1074/jbc.M112.427062. PMID 23678000. 
  7. ↑ "'Ryanopathy': causes and manifestations of RyR2 dysfunction in heart failure". Cardiovascular Research 98 (2): 240–7. May 2013. doi:10.1093/cvr/cvt024. PMID 23408344. 
  8. ↑ "Entrez Gene: RYR2 ryanodine receptor 2 (cardiac)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6262. 
  9. ↑ "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. January 2020. doi:10.1001/jamacardio.2019.5400. PMID 31913406. 
  10. ↑ "Cardiac ryanodine receptors control heart rate and rhythmicity in adult mice". Cardiovascular Research 96 (3): 372–80. December 2012. doi:10.1093/cvr/cvs260. PMID 22869620. 
  11. ↑ 11.0 11.1 11.2 11.3 "PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts". Cell 101 (4): 365–76. May 2000. doi:10.1016/S0092-8674(00)80847-8. PMID 10830164. 
  12. ↑ "Phosphorylation-dependent regulation of ryanodine receptors: a novel role for leucine/isoleucine zippers". The Journal of Cell Biology 153 (4): 699–708. May 2001. doi:10.1083/jcb.153.4.699. PMID 11352932. 
  13. ↑ "Association of sorcin with the cardiac ryanodine receptor". The Journal of Biological Chemistry 270 (44): 26411–8. November 1995. doi:10.1074/jbc.270.44.26411. PMID 7592856. 

Further reading

External links



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