Ryanodine receptor

Ryanodine receptors (RyR) are a family of intracellularly localized, membrane-bound calcium ion channels whose activation causes the release of calcium ions from the sarcoplasmic reticulum of striated muscle cells (skeletal muscle, heart muscle) into the cytosol. The RyR2-dependent Ca2+ release is essential for physiological contraction and relaxation and thus for systolic and diastolic heart function.

Three isoforms of ryanodine recpetors are distinguished:

• RyR1
• RyR2
• RyR3

The subtype RyR1 is mainly expressed in skeletal muscle and plays a key role in electromechanical coupling, but the receptor type is also found in the Purkinje cells of the cerebellum. In striated muscle, RYR1 is directly connected to the dihydropyridine receptors in the membrane of the transverse tubules. In case of a conformational change of the L-type calcium channels triggered by the action potential of the muscle, the RYR1 channels also open. This leads to the initial release of calcium ions from the sarcoplasmic reticulum into the cytosol of the muscle cell. RYR1 thus plays a key role in electromechanical coupling.

Mutations of the RYR1 gene are observed in central-core and multicore myopathy. They are an essential disposition for the development of malignant hyperthermia and can be inhibited by dantrolene, which is also the therapy of this disease.

The subtype RyR2 is expressed in the heart muscle. It is modulated by 4 identical subunits with enzymes associated with the respective subunits. Mutation of this receptor leads to catecholamine-ergic polymorphic ventricular tachycardia, an autosomal dominant inherited form of ventricular tachycardia associated with abnormal broadening of the QRS complex in the ECG, which can lead to syncope and ultimately to sudden cardiac death. Leaky RyR2 is the pharmacological target of new RyR-selective 1,4-benzothiazepine derivatives that stabilize the closed channel state by increased calstabin2 binding, prevent SR-Ca2+ leak and have shown therapeutic efficacy in arrhythmias and heart failure in vivo.

The subtype RYR3 is expressed in skeletal muscle during fetal development and neonatal period, but remains essentially confined to the brain in adults. The RYR3 receptor type may be involved in learning.

The ryanodine receptors derive their name from the alkaloid ryanodine, which was originally extracted from the plant Ryania speciosa (Salicaceae). Ryanodine was originally used as an insecticide. Ryanodine selectively binds to ryanodine receptors and blocks them.

Anti-RyR antibodies are used in 50% of cases in myasthenia gravis with thymoma (50%), but not in myasthenia gravis without thymoma. Other pathogenetically important antibodies are: acetylcholine receptor antibodies, titin antibodies, MuSK antibodies, LRP4 antibodies).