Calcium (Ca(2+))-activated chloride channels are fundamental mediators in numerous physiological processes including transepithelial secretion, cardiac and neuronal excitation, sensory transduction, smooth muscle contraction and fertilization. Despite their physiological importance, their molecular identity has remained largely unknown. Here we show that transmembrane protein 16A (TMEM16A, which we also call anoctamin 1 (ANO1)) is a bona fide Ca(2+)-activated chloride channel that is activated by intracellular Ca(2+) and Ca(2+)-mobilizing stimuli. With eight putative transmembrane domains and no apparent similarity to previously characterized channels, ANO1 defines a new family of ionic channels. The biophysical properties as well as the pharmacological profile of ANO1 are in full agreement with native Ca(2+)-activated chloride currents. ANO1 is expressed in various secretory epithelia, the retina and sensory neurons. Furthermore, knockdown of mouse Ano1 markedly reduced native Ca(2+)-activated chloride currents as well as saliva production in mice. We conclude that ANO1 is a candidate Ca(2+)-activated chloride channel that mediates receptor-activated chloride currents in diverse physiological processes.

Histamine provokes itching and is a major skin disease complaint. Histamine is known to excite a subset of sensory neurons, predominantly C-fibers. Although histamine is pruritogenic, its signaling pathways that excite sensory neurons have not been identified. Because the metabolic products of lipoxygenases (LOs) activate transient receptor potential vanilloid receptor-1 (TRPV1) in sensory neurons, we hypothesized that histamine excites sensory neurons by activating TRPV1 via phospholipase A 2 (PLA 2 ) and LO stimulation. In cultured sensory neurons, histamine evoked inward currents that were reduced by capsazepine, a TRPV1 blocker. Moreover, histamine provoked inward currents when histamine receptor subtype 1 (H1R) and TRPV1 were expressed heterologously, but not when H1R or TRPV1 was expressed alone. In addition, histamine caused Ca 2ϩ influxes in sensory neurons in wild-type mice but not in TRPV1 Ϫ/Ϫ mice. Furthermore, histamine caused a 2.5-fold increase in the production of 12-hydroxyeicosatetraenoic acid, a metabolite of LO, in cultured sensory neurons. When injected subcutaneously into the necks of mice, histamine caused bouts of scratching, which were greatly reduced by pretreatment with capsazepine, a TRPV1 blocker, and by inhibitors of PLA 2 , LO, and H1R. Furthermore, mice lacking TRPV1 markedly reduced histamine-induced scratching compared with wild type. Together, these results indicate that TRPV1 plays a key role in mediating the pruritogenic action of histamine via the PLA 2 /LO pathway.

Itch is one of the major complications of skin diseases. Although there are various substances that induce itch or pruritus, it is evident that histamine is the best known endogenous agent that evokes itch. Even though histamine-induced itch has been studied for some time, the underlying mechanism of itch is just beginning to emerge. Although various downstream signaling pathways of histamine receptors have been revealed, more studies are required to determine the cause of histamine-induced itch. It appears that itch and pain involve different neuronal pathways. Pain generally inhibits itch, which indicates an inter-communication between the two. Complex interactions between itch and pain may be expected based on reports on disease states and opioids. In this review, we discuss the molecular mechanism and the pharmacological aspects of histamine-induced itch. Especially, the underlying mechanism of TRPV1 (an anti-pruritus target) has been determined to some extent.

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