FIGURE 10.

Proposed schematic representation of Cl_Ca channel regulation by CaMKII and Ca²⁺-dependent and -independent phosphatases in pulmonary arterial smooth muscle cells. As intracellular Ca²⁺ levels rise in pulmonary artery smooth muscle cells, Cl_Ca channels are directly activated by Ca²⁺ and modulated by phosphorylation involving CaMKII and CaN Aα via Ca²⁺ binding to Ca²⁺-calmodulin and calcineurin B (CaN B). In the presence of ATP, CaMKII phosphorylation is favored over the effects produced by phosphatases. In the absence of ATP, this balance is shifted toward phosphatases, yielding up-regulation of I_Cl(Ca) following a transient state of phosphorylation due to consumption of the endogenous substrate. Under these conditions, dephosphorylation of I-1 by CaN Aα would relieve its inhibitory effect on PP1, which would then dephosphorylate the pore-forming or accessory subunit.