Junctophilins

Junctophilins are a family of membrane-associated proteins that form junctional membrane complexes by tethering the plasma membrane to the endoplasmic reticulum (ER) or sarcoplasmic reticulum (SR) in excitable cells. In mammals, four genes encode junctophilins: JPH1, JPH2, JPH3, and JPH4. JPH1 and JPH2 are prominently expressed in skeletal and cardiac muscle, where they support excitation–contraction coupling; JPH3 and JPH4 are enriched in the brain and participate in neuronal Ca2+ signaling.

All junctophilins share a similar domain organization. An N-terminal cytoplasmic region contains multiple MORN repeats that bind phospholipids at the inner surface of the plasma membrane, while a C-terminal region contains a transmembrane helix that anchors the protein in the ER/SR membrane. This architecture positions the ER/SR in very close proximity to the plasma membrane, forming junctional membrane complexes that align elements of the Ca2+ signaling machinery, including voltage-gated Ca2+ channels and ryanodine receptors.

Function and significance: The tethering function promotes efficient Ca2+-triggered Ca2+ release necessary for muscle contraction and rapid signaling in neurons. In muscle, junctophilins help align T-tubules with ryanodine receptors on the SR, enabling synchronous Ca2+ release during excitation-contraction coupling.

Clinical relevance: Genetic or functional disruption of JPH2 has been linked to familial cardiomyopathies, including hypertrophic and dilated forms. In the nervous system, mutations or expansions in JPH3 cause Huntington disease-like 2 (HDL2), a neurodegenerative condition. Altered junctophilin expression has also been observed in other neurological disorders, suggesting broader roles in Ca2+ homeostasis.