Figure 1.

Role of the angiotensin AT₂ receptor (AT₂R) in regulation of the apical Na⁺-Cl⁻ co-transporter (NCC) activity via inhibition of the basolateral 40-pS K⁺ channel (Kir4.1) activity. The Src family protein kinase, c-Src-, mediated phosphorylation of Kir4.1 is critically required for K⁺ retrieval. This process facilitates the activity of Na⁺-K⁺-ATPase (NKA) for maintaing the cell membrane potential and provides the driving force for Cl⁻ efflux via basolateral Cl⁻ channel (ClCk)-bartin. Cl⁻ efflux results in the decrease of [Cl⁻]_i and hyperpolarization of the basolateral membrane, which is rapidly sensed by with-no-lysine kinase (WNK). This results in the phosphorylation and activation of WNK and phosphorylation of Sterile 20/SPS-1-44-related proline-alanine-rich protein kinase (SPAK)/oxidative stress-related kinase (OSR1). These events are required for vesicular trafficking, phosphorylation, and efficient activity of NCC. However, the following several mechanisms require further elucidation: (a) whether the Src homology region 2 domain-containing phosphatase-1 (SHP-1) is involved in AT₂R mediated inhibition of c-Src and decrease in Kir4.1 activity; (b) elucidation of the molecular targets involved in WNK phosphorylation in response to the decrease in [Cl⁻]_i, (c) the role of the K⁺-Cl⁻-co-transporter and paracellular transport of anions in the maintenance of the membrane potential and [Cl⁻]_i, and (d) the lack of responsiveness of Kir4.1 to ang-II/AT₁R.