Ryanodine receptor Ca ²⁺ release channel post-translational modification: Central player in cardiac and skeletal muscle disease

Calcium release from internal stores is a quintessential event in excitation-contraction coupling in cardiac and skeletal muscle. The ryanodine receptor Ca ²⁺ release channel is embedded in the internal sarcoplasmic reticulum Ca ²⁺ store, which releases Ca ²⁺ into the cytoplasm, enabling contraction. Ryanodine receptors form the hub of a macromolecular complex extending from the extracellular space to the sarcoplasmic reticulum lumen. Ryanodine receptor activity is influenced by the integrated effects of associated co-proteins, ions, and post-translational phosphor and redox modifications. In healthy muscle, ryanodine receptors are phosphorylated and redox modified to basal levels, to support cellular function. A pathological increase in the degree of both post-translational modifications disturbs intracellular Ca ²⁺ signalling, and is implicated in various cardiac and skeletal disorders. This review summarises our current understanding of the mechanisms linking ryanodine receptor post-translational modification to heart failure and skeletal myopathy and highlights the challenges and controversies within the field.