Membrane-binding protein that provides a structural bridge between the plasma membrane and the sarcoplasmic reticulum and is required for normal excitation-contraction coupling in cardiomyocytes (PubMed:10949023, PubMed:19095005, PubMed:21339484). Provides a structural foundation for functional cross-talk between the cell surface and intracellular Ca(2+) release channels by maintaining the 12-15 nm gap between the sarcolemma and the sarcoplasmic reticulum membranes in the cardiac dyads (PubMed:10949023, PubMed:19095005, PubMed:21339484). Necessary for proper intracellular Ca(2+) signaling in cardiac myocytes via its involvement in ryanodine receptor-mediated calcium ion release (PubMed:10949023, PubMed:19095005, PubMed:21339484). Contributes to the construction of skeletal muscle triad junctions (PubMed:10949023). Transcription repressor required to safeguard against the deleterious effects of cardiac stress (PubMed:30409805). Generated following cleavage of the Junctophilin-2 chain by calpain in response to cardiac stress in cardiomyocytes (PubMed:30409805). Following cleavage and release from the membrane, translocates to the nucleus, binds DNA and represses expression of genes implicated in cell growth and differentiation, hypertrophy, inflammation and fibrosis (PubMed:30409805). Modifies the transcription profile and thereby attenuates pathological remodeling in response to cardiac stress (PubMed:30409805). Probably acts by competing with MEF2 transcription factors and TATA-binding proteins (PubMed:30409805). Interacts with TRPC3 (By similarity). Interacts with MEF2C (PubMed:30409805). The transmembrane domain is anchored in sarcoplasmic reticulum membrane, while the N-terminal part associates with the plasma membrane (PubMed:10949023). In heart cells, it predominantly associates along Z lines within myocytes (PubMed:10949023). In skeletal muscle, it is specifically localized at the junction of A and I bands (PubMed:10949023). Accumulates in the nucleus of stressed hearts. Abundantly expressed in skeletal muscle and heart (PubMed:10949023). Weak expression in stomach and lung (PubMed:10949023). At 9.5 dpc, it is expressed in the periphery of cardiac myocytes in the looped cardiac tube of the developing heart (PubMed:10949023). In skeletal muscle, expression increases during muscle maturation (PubMed:10949023). The MORN (membrane occupation and recognition nexus) repeats contribute to the plasma membrane binding, by interacting with phospholipids. Has affinity for phosphatidylserine, and phosphorylated phosphatidylinositols including PtdIns3P, PtdIns4P, PtdIns5P, PtdIns(3,5)P2 and PtdIns(3,4,5)P3. The bipartite nuclear localization signal (bNLS) and Ala-rich (alanine-rich; ARR) regions are involved in DNA-binding. Proteolytically cleaved by calpain in response to cardiac stress (PubMed:26063807). The major cleavage site takes place at the C-terminus and leads to the release of the Junctophilin-2 N-terminal fragment chain (JP2NT) (PubMed:26063807, PubMed:30409805). Phosphorylation on Ser-165, probably by PKC, affects RYR1-mediated calcium ion release, interaction with TRPC3, and skeletal muscle myotubule development. Null mice possess cardiomyocytes with deficiencies in the junctional membrane complexes and have abnormal Ca(2+) transients (PubMed:10949023, PubMed:19095005, PubMed:21339484). Mice die from cardiac arrest at 10.5 dpc (PubMed:10949023). Belongs to the junctophilin family.