FIGURE 2.

Differential activation of Ca²⁺-gated Cl^– channels in nociceptors. Overview of the distinct regulation of the Ca²⁺-gated Cl^– channels anoctamin and bestrophin. (A) Ano1 is found in a signaling complex together with GPCR, Caveolin-1 (Cav-1) and the Inositol-1,4,5 trisphosphate (IP₃) receptor in the membrane of the endoplasmic reticulum. This proximity of signaling molecules allows for a localized Ca²⁺ rise which is sufficient to activate the Cl^– channel Ano1, while the Ca²⁺ increase mediated by VGCCs does not affect anoctamin currents. Binding of phosphatidylinositol -4,5-bisphosphate (PIP₂) to anoctamin is necessary for channel opening under low Ca²⁺ concentration and prevents channel desensitization when Ca²⁺ concentration is high. Ano1 is further activated by heat and membrane depolarization. Direct interaction of TRPV1 and Ano1 leads to subsequent activation of anoctamin mediated by the TRPV1-induced depolarization and Ca²⁺ influx. Ano1 and TRPV1 act as peripheral heat sensors, but whether the full signaling complex exists at the peripheral nerve terminals has not been unequivocally shown so far. Additionally, the soluble N-terminus of chloride channel accessory (CLCA) increases surface availability of anoctamin. (B) In contrast to anoctamin, bestrophins can be activated by the Ca²⁺ influx through VGCCs and cell shrinkage.