Hypothetical models of EC coupling involving ANO1, Ca _V 1.2, and IP ₃ R during agonist-mediated contraction of mouse pulmonary arterial smooth muscle cells. (A) General uniform model depicting the activation of ANO1 by both Ca²⁺ release from IP₃-sensitive SR Ca²⁺ stores and Ca²⁺ entry through Ca_V1.2. In this model, the three ion transporters are evenly distributed in the membrane and are not physically coupled. The depolarization is maintained by the positive feedback loop established by Ca_V1.2-mediated activation of Cl⁻ efflux through ANO1 and its impact on the state of activation of Ca_V1.2 through regulation of membrane potential. (B) Schematic diagram illustrating the local interaction of ANO1, Ca_V1.2 with IP₃R and their impact on membrane potential, Ca²⁺ entry, and contraction. In this model, the three ion channels are physically coupled in a restricted number of sites (Super Cluster) distributed across the long axis of the cell (shown as red boxes in the bottom diagram) and are organized for compartmentalized Ca²⁺ signaling as highlighted by the yellow gradient area between the PM and segments of the SR in the close vicinity of the PM (top diagram). These compartmentalized areas serve the role of trigger sites for initiating Ca²⁺ waves that can then propagate through Ca²⁺-induced Ca²⁺ release (CICR). Ca²⁺ entry through Ca_V1.2, which is maintained by the depolarization caused by ANO1, supports the microenvironment that is necessary to promote the propagation of the Ca²⁺ waves by CICR and to reload SR Ca²⁺ stores. PASMC: pulmonary artery smooth muscle cell; IP₃: inositol-triphosphate; G_qPCR: G_q-protein coupled receptor; PLC: phospholipase C; SERCA2: type 2 Ca²⁺-ATPase of the SR.