Figure 9. Model of components involved in the generation of the divalent cation-induced Cl⁻ current in claudin-16-transfected MDCK-C7 cells.

Application of divalent cations to the basolateral side of claudin-16-expressing MDCK-C7 cell layers activates the Ca²⁺-sensing receptor, CaSR. This causes release of Ca²⁺ from intracellular stores and thus an increase in [Ca²⁺]_i. Intracellular Ca²⁺ activates the apical Ca²⁺-sensitive Cl⁻ channel bestrophin, which, in claudin-16-expressing cells, is recruited to the apical membrane and to the tight junction, i.e. close to the release sites of Ca²⁺ from intracellular stores. Cl⁻ enters the cells through basolateral Na⁺-dependent, K⁺-dependent or independent symport mechanisms and, under resting conditions, probably leaves the cells through basolateral, DIDS-sensitive Cl⁻ channels. When, upon CaSR stimulation, apical Cl⁻ channels open, Cl⁻ is able to leave the cells on the apical side, thus carrying the observed current. K⁺ entering the cells together with Cl⁻ on the basolateral side can leave the cells on the basolateral side through Ca²⁺-sensitive K⁺ channels. This helps to further enhance the observed divalent cation-induced current. This current changes the transepithelial potential and thus the driving force for both para- and transcellular transport of Mg²⁺ (and Ca²⁺).