RYR2 (ryanodine receptor 2; HGNC:10484, NCBI Gene ID 6262) is a human locus mapped to chromosome band 1q43 that encodes sarcoplasmic reticulum Ca2+ release channel RyR2 (4,967 aa per monomer; ~2.2 MDa tetramer). RYR2 acts in cardiac calcium-induced calcium release (CICR) & excitation-contraction coupling, together with SCN5A (Nav1.5 Cardiac Channel Gene), KCNH2 (hERG Potassium Channel Gene), and Beta-2 Adrenergic Receptor. Encodes the giant sarcoplasmic reticulum ryanodine receptor 2 governing cardiac calcium-induced calcium release.
Approved Symbol
RYR2
Chromosomal Locus
1q43
Encoded Product
Sarcoplasmic reticulum Ca2+ release channel RyR2 (4,967 aa per monomer; ~2.2 MDa tetramer)
Genomic Organization & Cytogenetic Locus: 105-exon mega-gene spanning ~790 kb on chromosome 1q43, encoding a 4,967-amino-acid subunit that assembles into a ~2.2-megadalton homotetrameric mushroom-shaped complex with a massive cytoplasmic foot domain bridged to calstabin-2 (FKBP12.6), calmodulin, calsequestrin-2, junctin, and triadin.
Cellular & Tissue Expression Profile: Localized at the junctional sarcoplasmic reticulum dyads of atrial and ventricular cardiac myocytes directly apposed to sarcolemmal L-type Cav1.2 voltage-gated calcium channels inside transverse tubules, as well as in hippocampal and cerebellar Purkinje neurons.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Mediates calcium-induced calcium release (CICR): a small trigger Ca2+ influx through L-type calcium channels during phase 2 of the cardiac action potential binds RyR2, opening the sarcoplasmic reticulum pore to release a large cytosolic Ca2+ transient that binds troponin C and initiates actomyosin cross-bridge cycling.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Heterozygous gain-of-function missense mutations clustering in four hotspot domains destabilize closed-state inter-subunit interactions and cause catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1), where beta-adrenergic PKA/CaMKII phosphorylation during exercise or stress triggers diastolic Ca2+ leak, delayed afterdepolarizations via the Na+/Ca2+ exchanger, and bidirectional ventricular tachycardia.
Therapeutic & Clinical Pharmacology: Clinically managed with non-selective beta-adrenergic blockers (nadolol, propranolol) and flecainide (which directly inhibits open-state RyR2 channels alongside Nav1.5), while RyR2-stabilizing rycals (such as ARM210) and AAV-mediated CRISPR allele-specific editing are in development.