junctophilin

Junctophilins are a family of membrane‑associated proteins that play a key role in forming and maintaining junctional membrane complexes (JMCs) between the plasma membrane and the endoplasmic or sarcoplasmic reticulum in excitable cells. Discovered in the early 2000s, the family includes three main isoforms in mammals: Junctophilin‑1 (JPH1), Junctophilin‑2 (JPH2), and Junctophilin‑3 (JPH3), each encoded by distinct genes and displaying tissue‑specific expression patterns. JPH1 is predominantly found in skeletal muscle, JPH2 in cardiac muscle, and JPH3 is expressed in neuronal tissues, especially in the brain.

Structurally, junctophilins possess an N‑terminal stretch of multiple MORN (membrane occupation and recognition nexus) motifs that bind to phospholipids of the plasma membrane, and a C‑terminal transmembrane segment that anchors the protein in the endoplasmic/sarcoplasmic reticulum membrane. This configuration bridges the two membranes, positioning voltage‑gated calcium channels and ryanodine receptors in close proximity, which facilitates rapid calcium signaling essential for muscle contraction and neuronal excitation.

Genetic mutations in JPH2 have been linked to hypertrophic cardiomyopathy and arrhythmogenic disorders, while expansions of a CAG repeat in JPH3 cause Huntington‑like disease 2 (HDL2), a neurodegenerative disorder. Experimental knockdown of junctophilins in animal models disrupts JMC formation, leading to impaired excitation‑contraction coupling and altered calcium homeostasis.

Research continues to explore junctophilins as potential therapeutic targets for cardiac and neurodegenerative diseases, given their central role in coupling electrical signals to intracellular calcium dynamics across a variety of cell types.