Ryanodine receptor 2 (RyR2)
The RYR2 gene encodes the ryanodine receptor type 2 that is expressed predominantly in the heart, brain, and smooth muscle. RyR2 is located in the endoplasmic or sarcoplasmic reticulum of muscle cells or neurons, and governs the release of calcium from intracellular calcium stores. RyR2-mediated calcium release plays an essential role in muscle contraction, membrane excitability, learning and memory.
Disease and/or Phenotype
Mutations in the RYR2 gene are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT) and calcium release deficiency syndrome (CRDS). Defective RyR2 function has also been associated with atrial fibrillation, cardiomyopathies, sudden cardiac death, and neurological disorders (for example, Alzheimer Disease).
Background and Genetics
Inventors at the University of Calgary have developed a collection of mouse models that harbor different RyR2 mutations, as below:
| RyR2 Mutation | Phenotype | Reference |
| RyR2-R4496C+/− mutant knock-in mice | RyR2-R4496C is a CPVT-causing mutation that enhances luminal calcium activation of RyR2 and the propensity for spontaneous calcium release also known as store-overload-induced Ca2+ release (SOICR) | 1 |
| RyR2-E4872Q+/− mutant Knock-in mice | RyR2-E4872Q is a luminal calcium sensing mutation that reduces the open time of the RyR2 channel and suppresses spontaneous calcium release or SOICR. The RyR2-E4872Q+/- mice are completely protected against Ca2+-triggered ventricular tachyarrhythmias (VTs) | 2 |
| RyR2-D4646A+/− mutant knock-in mice | RyR2-D4646A is a CRDS-associated mutation that markedly suppresses luminal calcium activation of RyR2, SOICR, and caffeine-induced calcium release. The RyR2-D4646A+/- mice display increased susceptibility to calcium alternans, early afterdepolarization, re-entrant arrhythmias, and pacing induced ventricular arrhythmias. | 3 |
| RyR2-T1365GFP Knock-in mice | This RyR2 mutant mice express a green fluorescence protein (GFP)-tagged RyR2. The GFP is inserted into RyR2 after residue T1365. Researcher can directly visualize RyR2 clusters in live and fixed ventricular myocytes and neruons. | 4 |
| RyR2-point mutation E4872Q in AD mouse model (5xFAD) background | This RyR2-E4872Q mutation upregulates hippocampal CA1-pyramidal cell A-type K+ current, a well-known neuronal excitability control that is downregulated in AD. | 5 |
Publication
- Zhou et al, 2011 – Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca2+ release – Med. 2011 Jul 10; 17(8): 1003–1009.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3268079/
- Chen et al, 2014 – The ryanodine receptor store sensing gate controls Ca2+ waves and Ca2+ triggered anemias – Med. 2014 Feb; 20(2): 184–192.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4269524/
- Sun et al, 2021 – Cardiac ryanodine receptor calcium release deficiency syndrome – Transl. Med. Vol 13, Issue 579
https://www-science-org.ezproxy.lib.ucalgary.ca/doi/pdf/10.1126/scitranslmed.aba7287
- Hiess et al., 2015 – Distribution and function of cardiac ryanodine receptor clusters in live ventricular monocytes, J Biol Chem.2015 Aug 14; 290(33): 20477–20487
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536453/
- Yao et al., 2020 — Limiting RyR2 Open Time Prevents Alzheimer’s Disease-Related Neuronal Hyperactivity and Memory Loss but Not β-Amyloid Accumulation, Cell Rep 2020 Sep 22;32(12):108169