2.A.49.2.3
The hepatocyte canalicular chloride channel/carrier, CLC-3 or CLCN3 of 818 aas with 11 TMSs in a 1 + 2 + 2 + 2 +2 + 2 TMS arrangement (I^- > Br^- > Cl^-); outward rectifying; inactivated at positive voltages (Shimada et al., 2000). Oxidation induces surface expression of ClC-3 and activation of ClC-3-dependent anion permeability (Kasinathan et al., 2007). It is swell-activated in human neutrophils during a respiratory burst (Ahluwalia, 2008). The ClC-3 Cl^-/H⁺ antiporter becomes uncoupled at low extracellular pH (Matsuda et al., 2010).  It transports superoxide, O₂^- (Hawkins et al. 2007; Fisher 2009). ClC-3 might be involved in modulating vascular remodeling in hypertension and arteriosclerosis (Guan et al. 2006). ClC-3 upregulation may protect against oxidative stress-induced necrosis (Remillard and Yuan 2005). The nine-member CLC gene family of Cl^- (chloride)-transporting membrane proteins is divided into plasma membrane-localized Cl^- channels and endo-/lysosomal Cl^-/H⁺ antiporters. Accessory proteins have been identified for ClC-K and ClC-2 channels and for the lysosomal ClC-7, but not previously for the other CLCs. TMEM9B (see TC# 8.A.123.1.4) is an interaction partner of ClC-3 and ClC-4 (but not ClC1 or ClC7), and this has implications for the physiological role of these transporters in neuronal endosomal homeostasis as well as for a better understanding of the pathological mechanisms in CLCN3- and CLCN4-related pathological conditions (Festa et al. 2024.