Abstract: Junctophilin-2 (JPH2) can connect and communicate T-tubule to sarcoplasmic reticulum in cardiomyocytes. JPH2 mutation or down-regulation has been found in hearts from hypertrophic cardiomyopathy, heart failure, and atrial fibrillation. Calpain, microtubules, and miRNA-24 are all involved in the regulation of JPH2 in cardiomyocytes. Up-regulation of JPH2 directly or indirectly protects cardiomyocytes, which may be beneficial for the repair of certain cardiac disease processes.