The junctophilin family of proteins: from bench to bedside

• Junctophilins are a conserved family of proteins found in all excitable cells.
• Junctophilins maintain subcellular architecture and calcium signaling.
• Mutations have been linked to cardiomyopathy, arrhythmia, and neurodegeneration.

Excitable tissues rely on junctional membrane complexes to couple cell surface signals to intracellular channels. The junctophilins have emerged as a family of proteins critical in coordinating the maturation and maintenance of this cellular ultrastructure. Within skeletal and cardiac muscle, junctophilin 1 and junctophilin 2, respectively, couple sarcolemmal and intracellular calcium channels. In neuronal tissue, junctophilin 3 and junctophilin 4 may have an emerging role in coupling membrane neurotransmitter receptors and intracellular calcium channels. These important physiological roles are highlighted by the pathophysiology which results when these proteins are perturbed, and a growing body of literature has associated junctophilins with the pathogenesis of human disease.