Ryanodine receptor 1 and 2 (RYR1/RYR2)

Ryanodine receptors (RyRs) are massive, homotetrameric intracellular calcium release channels located in the sarcoplasmic reticulum (SR) membrane, playing a fundamental role in muscle physiology [1, 2]. Ryanodine receptor 1 (RYR1) is primarily expressed in skeletal muscle, where it is physically coupled to the dihydropyridine receptor to trigger contraction in response to membrane depolarization [4, 11]. Ryanodine receptor 2 (RYR2) is the dominant isoform in cardiac muscle, mediating calcium-induced calcium release (CICR) to synchronize heartbeats [5, 10]. Mutations in RYR1 are the primary cause of malignant hyperthermia, a life-threatening reaction to volatile anesthetics, and congenital myopathies such as central core disease [1, 18]. RYR2 mutations are linked to stress-induced arrhythmias, including catecholaminergic polymorphic ventricular tachycardia (CPVT) and heart failure [2, 6]. Pharmacological targeting of RyRs includes the use of dantrolene as an RYR1 antagonist for malignant hyperthermia and the development of stabilizers like ARM210 to prevent pathological calcium leaks [6, 19]. These receptors are critical therapeutic targets for managing both inherited and acquired disorders of muscle and cardiac function [13, 17].

Other names

Skeletal muscle calcium release channelCardiac muscle calcium release channelRyR1RyR2MHS1ARVD2CPVT1RYDRSKRRVTSIPVACRDS

Drugs targeting these receptors primarily act as antagonists to block excessive calcium release or as stabilizers (Rycals) that enhance the binding of calstabin proteins to the receptor complex, thereby preventing pathological calcium leaks from the sarcoplasmic reticulum [6, 19].