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Preprint WatchMildOctober 30th, 2026

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

Palfrey, C.; Grayston, J.; Zhang, X.; Gao, Y.; Figoli, S.; Dougherty, L.; Chen, Z.; Prato, V.; Jones, F.; Milne, S.; Gao, H.; Shapiro, M.; Gamper, N.; Shah, S.

Extended Synaptotagmin-1 acts as a calcium-responsive scaffold organising ER to plasma membrane nanodomains, and its knockdown reduces bradykinin-evoked ANO1 activity, store-operated calcium entry and nocifensive behaviour in vivo.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

A bioRxiv preprint identifies Extended Synaptotagmin-1 as a calcium-responsive scaffold organising ER to plasma membrane nanodomains in nociceptive dorsal root ganglion neurons, reporting that its knockdown reduced bradykinin-evoked ANO1 activity, impaired store-operated calcium entry and reduced bradykinin-induced nocifensive behaviour in vivo. The Claidex graph holds one ANO1 failure, gdc-6988-ano1-tmem16a-bronchiectasis-copd-phase1-sponsor-termination, a Phase 1 programme closed by sponsor decision in airway disease. Severity is mild because that termination carries no mechanistic information about the target and the indications do not overlap. What the preprint adds is a claim that ANO1 activity in sensory neurons depends on an upstream scaffold for its calcium supply, which would matter to any programme assuming that direct ANO1 blockade is by itself sufficient to modulate the pathway.

Abstract excerpt

Endoplasmic reticulum-plasma membrane (ER-PM) junctions coordinate Ca2+ signalling and nociceptor excitability during inflammation, but the molecular scaffold governing assembly of signalling complexes remains unclear. Here, we identify Extended Synaptotagmin-1 (Esyt1) as a key, dynamic regulator of inflammatory pain signalling. In nociceptive DRG neurons, Esyt1 is co-expressed with ANO1 and IP3R1. Time-resolved proximity ligation assays and super-resolution microscopy showed that bradykinin rapidly increased ANO1-Esyt1 nanoscale proximity, while IP3R1-Esyt1 interactions were dynamically reorganised during ANO1-IP3R1 complex formation. Esyt1 knockdown reduced bradykinin-evoked ANO1 activity, impaired store-operated Ca2+ entry (SOCE), decreased STIM1-Orai1 complex formation, and disrupted ER Ca2+ store refilling. Simultaneous imaging of Ca2+ dynamics and ANO1 activity demonstrated functional coupling between SOCE and ANO1 that required Esyt1. Furthermore, in-vivo Esyt1-knockdown significantly reduced bradykinin-induced nocifensive behaviour. Together, these findings identify Esyt1 as a Ca2+-responsive scaffold that organises ER-PM signalling nanodomains and promotes inflammatory pain signalling.

Matching Claidex post-mortems

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This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.