Junctophilin-4 is essential for signalling at plasma membrane-endoplasmic reticulum junctions in sensory neurons

Junctions of endoplasmic reticulum and plasma membrane (ER-PM junctions) serve as signaling hubs in prokaryotic cells. ER-PM junctions are present in peripheral sensory neurons and are necessary for pro-inflammatory G protein coupled receptor signalling and for inflammatory pain generation. Yet, the principles of ER-PM junctions assembly and maintenance, as well as their role in inflammatory signaling in sensory neurons are only beginning to emerge. Here we discovered that a member of the junctophilin family of proteins, JPH4, is abundantly expressed in rat dorsal root ganglion (DRG) neurons and is necessary for the formation of store operated Ca 2+ entry (SOCE) complex at the ER-PM junctions in response to the G-protein induced ER Ca 2+ store depletion. Furthermore, we demonstrate a key role of the JPH4 and ER Ca 2+ stores in the maintenance of inflammatory pain. Indeed, knockdown of JPH4 expression in DRG in vivo significantly reduced the duration of pain produced by inflammatory mediator bradykinin. Since the ER supplies Ca 2+ for the excitatory action of multiple inflammatory mediators, we suggest that junctional Ca 2+ signalling maintained by JPH4 is an important contributor to the inflammatory pain mechanisms.