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

Abstract

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.

Keeping pain away by distancing the plasma membrane from the endoplasmic reticulum

“…Overall, the study by Hogea et a.l (2021) provides the first demonstration of the role of junctophilins in store operated Ca 2+ entry in peripheral sensory neurons, and demonstrates their role in inflammatory pain.…”

“…In this issue of The Journal of Physiology , Hogea et al . (2021) address the role of junctophilins in nociceptive DRG neurons. The authors stained rat DRG neurons with antibodies against all four junctophilin isoforms (JPH1‐4), and identified junctophilin‐4 as the dominant isoform, with some expression of JPH1 and JPH3, but not JPH2.…”

Insight on novel mechanisms mediating the generation of inflammatory pain in somatosensory neurons

“…In a recent publication in the Journal of Physiology, Hogea et al (2021) characterised the role of junctophilins in SOCE in DRG somatosensory neurons and investigated their potential involvement in inflammatory pain in vitro and in vivo. The authors first aimed to identify which isoforms of the JPH, STIM and Orai families were expressed in primary sensory neurons.…”

“…Finally, to determine whether JPH-4 is involved in pain perception, Hogea et al (2021) delivered cholesterol-conjugated JPH-4 siRNA to the lumbar region (L5-L6) of adult rats to silence JPH-4 gene expression and performed behavioural experiments. Intraplantar injection of BK induces inflammation and nocifensive behaviour in rodents.…”