Super-resolution insights into the role of Esyt1 in ER-PM junction dynamics in sensory neurons

In sensory neurons, the plasma membrane (PM)-resident Ca2+-activated Cl− channel Anoctamin 1 (ANO1 or TMEM16A) amplifies noxious (nociceptive) signalling through functional coupling to endoplasmic reticulum (ER) Ca2+ stores via inositol triphosphate receptors (IP3R). The intrinsically low Ca2+ sensitivity of ANO1 demands highly localised, micromolar Ca2+ signals for activation, therefore, maintaining nanodomain proximity between ANO1 and IP3R1 at ER-PM contact sites (junctions) is essential. As a Ca2+-sensitive junctional tether, extended synaptotagmin 1 (Esyt1) is an intriguing candidate to facilitate the dynamic formation and maintenance of ANO1-containing ER-PM nanodomains.