Ca2+ activated Cl− channels as targets for analgesics

The protein Discovered On Gastrointestinal stromal tumors (GIST) protein 1 (DOG1) is a biomarker used in the diagnosis of this type of neoplasm. Nevertheless, high DOG1 expression levels cannot only be detected in GIST, but also in a considerable number of other tumors [1]. DOG1 is also known as ANOctamin 1 (ANO1) and TransMEMbrane protein with unknown function 16A (TMEM16A) and belongs to a superfamily of proteins that operate either as Ca2+-activated Clchannels (CaCCs) or as phospholipid scramblases. CaCCs formed by these proteins may subserve a variety of biological functions that include, for instance, blood pressure regulation, lung ventilation, saliva production and intestinal Clsecretion [1]. Anoctamins are also involved in tumorigenesis and tumor proliferation, but whether these actions are related to a channel mode of operation remains controversial. Nevertheless, in several instances ANO1 channel blocking agents were found to reduce tumor progression [1]. A recent addition to this list of anoctamin functions is pain perception. First, ANO1 was revealed to contribute to the mechanisms that underlie the algogenic action of bradykinin: the peptide was reported to activate depolarizing currents through ANO1 in nociceptive neurons by releasing Ca2+ from the endoplasmic reticulum (Figure 1) [2]. Bradykinin and numerous other signaling molecules, such as protons, prostanoids, nucleotides, histamine, and serotonin, are released from cells surrounding the nociceptors under conditions of tissue damage and inflammation. Together, these mediators are termed “inflammatory soup” and as such they are known to enhance the excitability of sensory neurons. The combined action of an experimental inflammatory soup containing bradykinin, prostaglandin E2, histamine, and serotonin on the excitability of nociceptive neurons was largely attenuated or even abolished when these neurons did not express ANO1 [3]. Most recently, serotonin on its own has been shown to excite nociceptive sensory neurons through an activation of CaCCs [4]. This action was mediated by 5HT2C receptors and did also involve an activation of TRPV1 channels. This confirmed previous Editorial