Junctophilin-2 (JPH2)

Junctophilin-2 (JPH2) is a structural membrane-binding protein essential for the formation and maintenance of junctional membrane complexes that link the plasma membrane (especially the T-tubule in muscle) and the sarcoplasmic/endoplasmic reticulum in excitable cells. It is highly expressed in cardiac, skeletal, and some smooth muscle tissues. By maintaining the critical nanoscale gap (~12–15 nm) between the sarcolemma and the sarcoplasmic reticulum, JPH2 enables the close apposition of voltage-gated L-type calcium channels (CaV1.1 and CaV1.2) and ryanodine receptors, which is required for rapid and robust excitation–contraction coupling[1][4]. Mutations or cleavage of JPH2 are linked to major cardiac diseases, notably hypertrophic and dilated cardiomyopathy and heart failure[1][2][4]. Recent research also shows that JPH2 acts as a double-stranded RNA-binding protein that can regulate innate immune responses specifically in cardiomyocytes by sequestering dsRNA away from cytosolic sensors, thus preventing inappropriate activation of antiviral defense pathways[3]. JPH2 structure includes N-terminal MORN (Membrane Occupation and Recognition Nexus) repeats involved in membrane/lipid and protein interactions, a central α-helical domain, a flexible region, and a C-terminal transmembrane helix that anchors it in the sarcoplasmic reticulum membrane[1]. Cleavage by calpain disrupts its function in the heart, and the N-terminal fragment may also act as a nuclear transcriptional regulator during heart failure[2].

Other names

Junctophilin-2 N-terminal fragmentJP2JP-2JP2NTjunctophilin2CMD2ECMH17junctophilin type 2junctophilin-2

Calpain inhibitors (e.g., calpain-1 and calpain-2 inhibitors) may prevent JPH2 cleavage and preserve excitation–contraction coupling, indirectly targeting JPH2[2]