Figure 7.

Schematic representation of ClC-3 Cl⁻ channels in VSMCs. ClC-3, a member of voltage-gated ClC Cl⁻ channel family, encodes Cl⁻ channels in vascular smooth muscle cells that are volume regulated (I_Cl,vol) and can be activated by cell swelling (I_Cl,swell) induced by exposure to hypotonic extracellular solutions or possibly membrane stretch. I_Cl,b is a basally activated ClC-3 Cl⁻ current. α-helices of ClC-3 are shown as a–r. ClC-3 proteins are expressed on both sarcolemmal membrane and intracellular organelles including mitochondria (mito) and endosomes. The proposed model of endosome ion flux and function of Nox1 and ClC-3 in the signaling endosome is adapted from Miller Jr. et al. (115). Binding of IL-1β or TNF-α to the cell membrane initiates endocytosis and formation of an early endosome (EEA1 and Rab5), which also contains NADPH oxidase subunits Nox1 and p22phox, in addition to ClC-3. Nox1 is electrogenic, moving electrons from intracellular NADPH through a redox chain within the enzyme into the endosome to reduce oxygen to superoxide. ClC-3 functions as a chloride-proton exchanger, required for charge neutralization of the electron flow generated by Nox1. The ROS generated by Nox1 result in NF-κB activation. Both ClC-3 and Nox1 are necessary for generation of endosomal reactive oxygen species (ROS) and subsequent NF-κB activation by IL-1β or TNF-α in VSMCs. Statins block ClC-3 channels, which causes hyperpolarization of the cell membrane, closure of Ca²⁺ channels and vasorelaxation, and inhibition of cell proliferation. PKC, protein kinase C; PP, serine-threonine protein phosphatases; α–AR, α-adrenergic receptor; Gi, heterodimeric inhibitory G protein. Nox: NADPH oxidase (59). (Copyright Request: Duan, Hypertension, 2010)