This website was created as an assignment for Genetics 564 at the University of Wisconsin-Madison
Ryanodine Receptor 2
The Ryanodine Receptor 2 protein is a 4967 amino acid sequence. RYR2 works in a tetrad along side FKBP1A, FKBP1B, CALM, S100A, PKA, PRKAR2A, AKAP6, PP2A and PP1 proteins to form the calcium ion channel in cardiac tissue. RYR2 protein anchors itself into the outer membrane of the sacroplasmic reticulum[1]. This specialized organelle, only found in muscle tissue, is responsible for retaining calcium ions until needed for contraction. When calcium ions are released from the sacroplasmic reticulum and into the cytoplasm of the muscle cell via the calcium ion channel, the muscle cell will contract.
Mutations in the RYR2 gene results in a misscoding of the amino acids. These amino acid changes directly affect the amino-amino interactions necessary for proper folding as well as RYR2's capability of properly interacting with the many other proteins that make up the the calcium ion channel. These mutations cause a leaky RYR2 protein to be produced and results in RYR2's inability to regulate the amount of calcium ions being released into the cytoplasm. The results of a defective RYR2 protein are very noticeable in an ECG by the premature ventricular contractions[5].
The RYR2 protein has been found to be positively regulated by a adrenergic receptor signaling pathway. Adrenaline from the brain can activate adenylyl cyclase which transforms ATP into cyclic AMP or (cAMP). cAMP is responsible for activating protein kinase A (PKA) which phosphorylates RYR2 and causes it to become ultra sensitive to calcium ion. This pathway activation causes cardiac muscle to contract [3,4] This makes sense because adrenaline is involved in the sympathetic nervous system and the fight or flight response. This response is a survival mechanism that is activated when danger is sensed. It increases the heart rate in order to provide more oxygen to muscles and brain to prepare oneself to fight off the danger or flee[4]. This pathway can also help us understand why symptoms of CPVT are only present during exercise and during intense emotion as adrenaline and norepinephrine are released from the adrenal gland during both of these situations.
A common treatment for CPVT is prescribing beta-blockers. Beta blockers help regulate adrenal neurotransmitters such as norepinephrine and epinephrine (adrenaline) which are responsible for increasing heart rate. The beta blocker binds to the neurotransmitter receptors in the nerve tissue and prevents any signal from being transmitted to the heart. The beta blocker interferes with the adrenergic receptor signaling pathway and prevents RYR2 hypersensitivity to calcium[2].
References:
[1] Uniprot: http://www.uniprot.org/uniprot/Q92736
[2] Marks, Jay W. MedicineNet. Retrieved March 5, 2014, from http://www.medicinenet.com/beta_blockers/article.htm
[3] Gene Ontology: http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0086094
[4] Adenylyl Cyclase. Retrieved March 7, 2013, from http://webspace.ship.edu/cgboer/genpsyneurotransmitters.html
[5]US. National Library of Medicine. (2009). Electronic References. Retrieved February 1, 2014 from
http://ghr.nlm.nih.gov/gene/RYR2
Image:http://physiologyonline.physiology.org/content/22/5/342
[1] Uniprot: http://www.uniprot.org/uniprot/Q92736
[2] Marks, Jay W. MedicineNet. Retrieved March 5, 2014, from http://www.medicinenet.com/beta_blockers/article.htm
[3] Gene Ontology: http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0086094
[4] Adenylyl Cyclase. Retrieved March 7, 2013, from http://webspace.ship.edu/cgboer/genpsyneurotransmitters.html
[5]US. National Library of Medicine. (2009). Electronic References. Retrieved February 1, 2014 from
http://ghr.nlm.nih.gov/gene/RYR2
Image:http://physiologyonline.physiology.org/content/22/5/342
Site created by: Mercede Davis
Email contact: [email protected]
Date last updated: 5/14/14
Genetics 564, University of Wisconsin-Madison
Email contact: [email protected]
Date last updated: 5/14/14
Genetics 564, University of Wisconsin-Madison