*2.3. Anoctamin 1*

ANO1 is a calcium-activated chloride channel [5–7]. Although the ANO family includes ten subtypes, only ANO1 and ANO2 exhibit marked activity as calcium-activated chloride channels, and conductance of ANO1 is larger than ANO2. The crystal structure of fungal ANO has recently been determined at high resolution [87]. Furthermore, the dimer structure of mouse ANO1 (which contains ten TM regions in one subunit) has been clarified by cryo-electron microscopy [88,89]. Accordingly, the calcium binding site was shown to be encompassed by TM6 to TM8. Interestingly, each ANO1 subunit has one pore region surrounded by TM3 to TM8. Structural analysis showed that the dynamic movement of TM6 may be critical for calcium-mediated channel opening.

Although ANO1 can be activated by global increases in intracellular calcium via activation of voltage-gated calcium channels, ANO1 activation through GqPCR is also likely to be important due to direct interactions between ANO1 and IP3R in endoplasmic reticulum calcium stores [10,90]. Therefore, ANO1 is possibly involved in nociception induced by inflammatory factors such as bradykinin [91]. ANO1 is also activated by noxious heat in DRG neurons and induces a burning pain sensation [8]. These characteristics may explain why chloride channel activity evokes neural excitation in primary sensory neurons, in that higher intracellular chloride concentrations can be maintained as the equilibrium potential in these cells is more positive than the resting potential in DRG neurons [11].

#### **3. Collaboration of Ion Channels**

Although each ion channel, including TRP channels, independently work as detectors of nociceptive stimuli, some ion channels make physical or functional complexes that are critically involved in pain sensation. In this part, we summarize ion channel interactions and nociceptor populations according to recent reports (Figure 1).
