Ryanodine receptor 2

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.

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. RYR2 channels are associated with many cellular functions, including mitochondrial metabolism, gene expression and cell survival, in addition to their role in cardiomyocyte contraction.

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."

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

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. 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.

Interactions

Ryanodine receptor 2 has been shown to interact with:

• Protein kinase A (AKAP6, PRKACA, PRKACB,)
• CaMKII (via phosphorylation at serine positions S2808 and S2814 in humans and rodents, S2809 and S2815 in rabbits)
• SRI
• Protein phosphatase 1 (dephosphorylation at serine positions S2808 and S2814 in rodents)
• Protein phosphatase 2 (dephosphorylation at serine position S2814 in rodents)

References

References

1. (August 1990). "Molecular cloning of cDNA encoding the Ca2+ release channel (ryanodine receptor) of rabbit cardiac muscle sarcoplasmic reticulum". The Journal of Biological Chemistry.
2. (August 1993). "Chromosome mapping of five human cardiac and skeletal muscle sarcoplasmic reticulum protein genes". Genomics.
3. (February 2001). "Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2)". Human Molecular Genetics.
4. (June 2010). "Kinetics of FKBP12.6 binding to ryanodine receptors in permeabilized cardiac myocytes and effects on Ca sparks". Circulation Research.
5. "Q92736 - RYR2_HUMAN".
6. (June 2013). "Cardiomyocyte ATP production, metabolic flexibility, and survival require calcium flux through cardiac ryanodine receptors in vivo". The Journal of Biological Chemistry.
7. (May 2013). "'Ryanopathy': causes and manifestations of RyR2 dysfunction in heart failure". Cardiovascular Research.
8. "Entrez Gene: RYR2 ryanodine receptor 2 (cardiac)".
9. (March 2020). "Identification of a Novel Homozygous Multi-Exon Duplication in RYR2 Among Children With Exertion-Related Unexplained Sudden Deaths in the Amish Community". JAMA Cardiology.
10. (December 2012). "Cardiac ryanodine receptors control heart rate and rhythmicity in adult mice". Cardiovascular Research.
11. (May 2001). "Phosphorylation-dependent regulation of ryanodine receptors: a novel role for leucine/isoleucine zippers". The Journal of Cell Biology.
12. (May 2000). "PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts". Cell.
13. (June 1991). "Unique phosphorylation site on the cardiac ryanodine receptor regulates calcium channel activity". The Journal of Biological Chemistry.
14. (April 2004). "Ca2+/calmodulin-dependent protein kinase II phosphorylation regulates the cardiac ryanodine receptor". Circulation Research.
15. (November 1995). "Association of sorcin with the cardiac ryanodine receptor". The Journal of Biological Chemistry.