Activation of the Cl- channel ANO1 by localized calcium signals in nociceptive sensory neurons requires coupling with the IP3 receptor.

We report that anoctamin 1 (ANO1; also known as TMEM16A) Ca 2+ -activated Cl − channels in small neurons from dorsal root ganglia are preferentially activated by particular pools of intracellular Ca 2+ . These ANO1 channels can be selectively activated by the G protein–coupled receptor (GPCR)–induced release of Ca 2+ from intracellular stores but not by Ca 2+ influx through voltage-gated Ca 2+ channels. This ability to discriminate between Ca 2+ pools was achieved by the tethering of ANO1-containing plasma membrane domains, which also contained GPCRs such as bradykinin receptor 2 and protease-activated receptor 2, to juxtamembrane regions of the endoplasmic reticulum. Interaction of the carboxyl terminus and the first intracellular loop of ANO1 with IP 3 R1 (inositol 1,4,5-trisphosphate receptor 1) contributed to the tethering. Disruption of membrane microdomains blocked the ANO1 and IP 3 R1 interaction and resulted in the loss of coupling between GPCR signaling and ANO1. The junctional signaling complex enabled ANO1-mediated excitation in response to specific Ca 2+ signals rather than to global changes in intracellular Ca 2+ .