Activation of the Cl Channel ANO1 by Localized Calcium Signals in Nociceptive Sensory Neurons Requires Coupling with the IP3 Receptor
Positioning of an excitatory channel where the endoplasmic reticulum and plasma membrane meet enables pain sensing neurons to distinguish among calcium signals. Insulating Pain Signals Activation of damage sensing neurons evokes pain. Jin et al. describe a mechanism by which the depolarizing chloride channel anoctamin 1 (ANO1) is coupled only to those calcium signals that arise from activation of proinflammatory G protein (heterotrimeric guanine nucleotide binding protein) coupled receptors (GPCRs) rather than by global calcium signals mediated by voltage gated calcium channels (VGCCs) ANO1, which is present in the plasma membrane, was found in a lipid raft based complex that contained the activating GPCRs and the endoplasmic reticulum (ER) resident calcium channel, IP3R1 (inositol 1,4,5 trisphosphate receptor 1) The interaction of ANO1 with IP3R1 and the ability of the local calcium signals to stimulate ANO1 activity were lost when lipid microdomains were chemically disrupted. Instead, ANO1 became receptive to VGCC activation in the absence of lipid rafts. Thus, a plasma membrane ER microdomain complex limits activation of nociceptive neurons to only the appropriate signals. We report that anoctamin 1 (ANO1; also known as TMEM16A) Ca2+ activated Cl channels in small neurons from dorsal root ganglia are preferentially activated by particular pools of intracellular Ca2+ These ANO1 channels can be selectively activated by the G protein coupled receptor (GPCR) induced release of Ca2+ from intracellular stores but not by Ca2+ influx through voltage gated Ca2+ channels. This ability to discriminate between Ca2+ 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 IP3R1 (inositol 1,4,5 trisphosphate receptor 1) contributed to the tethering. Disruption of membrane microdomains blocked the ANO1 and IP3R1 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 Ca2+signals rather than to global changes in intracellular Ca2+
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