Peripheral nociceptive (‘pain’) neurons are primary sensors of tissue damage. One group of chemical stimuli that can excite these neurons and cause pain is the ligands of pro-inflammatory G protein coupled receptors (GPCR) that activate phospholipase C and induce release of Ca2+ from the intracellular stores. This class of GPCR includes bradykinin B2 receptor and protease activated receptor-2 (PAR2). Among several cellular targets of such receptors is Ca2+ activated Cl- channel ANO1 (TMEM16A), which depolarizes and excites nociceptive neurons as these accumulate high intracellular Cl- concentrations (1, 2). Since many types of Ca2+ signals exit in neurons, nociceptive neurons must be able to identify Ca2+ signals originating specifically from the potentially damaging stimulus while ignoring ‘irrelevant’ Ca2+ signals. We found that ANO1 in nociceptive dorsal root ganglion (DRG) neurons exists as a part of a signaling complex that also includes B2 and/or PAR2 receptors (3). The complex is assembled at the junctions between plasma membrane and endoplasmic reticulum (ER) and ensures close apposition (and physical association) of plasma membrane ANO1 channels and ER’s IP3 receptors; the later serve as sources of Ca2+ for the activation of ANO1 in response to PAR2 or B2 receptor triggering. We further hypothesize that these ANO1-containing junctional microdomains may create a local environment that is poorly accessible for cytosolic Ca2+ ions that do not originate from the ER, thus protecting ANO1 from ‘irrelevant’ Ca2+ signals. Indeed, we found that ANO1 channels couple poorly to the Ca2+ influx through the voltage-gated Ca2+ channels or TRPV1. Disruption of these ANO1-containing complexes (e.g. by disrupting interaction of ANO1 with the IP3 receptors) results in ‘promiscuous’ activation of ANO1 by global cytosolic Ca2+ signals which, in turn, makes nociceptive DRG neurons more excitable (3). Similar ANO1 signaling complexes may exist in other neurons and non-neuronal cells. For example, in smooth muscle cells a close association of endogenous Ca2+ activated Cl- channels and ryanodine receptors has been hypothesized (4). In sum, we suggest that in nociceptive DRG neurons and possibly in some other cell types there are specific signaling complexes, which bring together ANO1, GPCRs, and ER-localized IP3 receptors. These complexes may serve to ensure the fidelity of GPCR signaling.