Junctophilin-2 (JP2) is a key structural protein of junctional membrane complexes (JMCs) that stabilize contacts between the sarcoplasmic reticulum and transverse tubules required for excitation-contraction (EC) coupling in cardiomyocytes. Under pathophysiological conditions, the intracellular cysteine protease Calpain activated by disturbed intracellular Ca2+ homeostasis cleaves JP2 and, hence, disturbs EC coupling. In return, the primary N-terminal JP2 cleavage fragment (NT1) translocates into the nucleus, where it accumulates in dense local spots associated with gene-rich euchromatin and proposedly acts as a cardioprotective transcriptional regulator in heart failure. Secondary cleavage events by Calpain or other proteases may further alter the function of JP2. After recently revealing the complete spectrum of JP2 cleavage fragments generated by Calpain proteolysis, we provide here an update about the position of the Calpain cleavage sites relative to the structural environment of JP2 in JMCs and how heart disease-associated gene variants of JP2 could affect the proteolytic regulation by Calpain.
Calcium, Calpain, Cardiomyocyte, Junctophilin-2, Ryanodine Receptor