Junctional Nanodomains Organised by Extended Synaptotagmin-1 Underlie Inflammatory Signalling in Sensory Neurons

In nociceptive Rattus norvegicus DRG neurons, Esyt1 knockdown reduces bradykinin-evoked ANO1 activity and inflammatory nocifensive behaviour, linking Esyt1 to ER–PM signalling nanodomains.

• Why it matters: ER–PM junctions coordinate Ca2+ signalling and nociceptor excitability during inflammation, but the molecular scaffold assembling signalling complexes was unclear.
• What they did: Using time-resolved proximity ligation assays and super-resolution microscopy, bradykinin rapidly increased ANO1–Esyt1 proximity and reorganised IP3R1–Esyt1 interactions during ANO1–IP3R1 complex formation; Esyt1 knockdown was tested with Ca2+ imaging, SOCE readouts, and in-vivo nocifensive assays.
• The result: Esyt1 is a Ca2+-responsive scaffold that organises ER–PM signalling nanodomains, promoting SOCE, STIM1–Orai1 complex formation, ER Ca2+ store refilling, and bradykinin-driven inflammatory pain signalling.