Junctional Nanodomains Organised by Extended Synaptotagmin-1 Underlie Inflammatory Signalling in Sensory Neurons
- 1University of Leeds
Abstract
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.
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BibTeX
@misc{palfrey2026junctional,
title = {{Junctional Nanodomains Organised by Extended Synaptotagmin-1 Underlie Inflammatory Signalling in Sensory Neurons}},
author = {C. Palfrey and J. Grayston and X. Zhang and Y. Gao and S. Figoli and L. Dougherty and Z. Chen and V. Prato and F. Jones and S. Milne and H. Gao and M. Shapiro and N. Gamper and S. Shah},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.28.762450},
url = {https://www.biorxiv.org/content/10.64898/2026.10.28.762450v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Junctional Nanodomains Organised by Extended Synaptotagmin-1 Underlie Inflammatory Signalling in Sensory Neurons
AU - C. Palfrey
AU - J. Grayston
AU - X. Zhang
AU - Y. Gao
AU - S. Figoli
AU - L. Dougherty
AU - Z. Chen
AU - V. Prato
AU - F. Jones
AU - S. Milne
AU - H. Gao
AU - M. Shapiro
AU - N. Gamper
AU - S. Shah
PY - 2026
DA - 2026/10/28
PB - bioRxiv
DO - 10.64898/2026.10.28.762450
UR - https://www.biorxiv.org/content/10.64898/2026.10.28.762450v1
AB - 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.
ER -