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After a description of the biophysical, regulation, and molecular properties of CaCCs in PASMCs and other vascular myocytes, this review focuses on the various sources of Ca2+ triggering CaCCs and how they might affect the control of membrane potential and pulmonary arterial tone under physiological and pathophysiological conditions. Biophysical properties of CaCCs in PASMCs General macroscopic properties of Ca2+-activated Cl? currents CaCCs exhibit complex biophysical properties dictated by the interplay of Ca2+-, voltage-, and time-dependent gating mechanisms. Adding to this complexity are recent findings demonstrating that the channels in VSMCs are also regulated by phosphorylation involving both Ca2+-dependent and Ca2+-independent kinases and phosphatases. Initial studies describing the properties of CaCCs in smooth Ceramidase muscle and other cell types investigated with the whole-cell recording variant of the patch-clamp technique used transient sources of Ca2+ to activate the channels (e.g., Ca2+ entry via Ca2+ channels or Ca2+ release from internal stores). Although such methods suggested that Ca2+ plays an obligatory role in activating CaCCs, they provided little information on the biophysical properties of CaCCs, because only one of the three main variables controlling CaCC gating, voltage, was clamped, while internal Ca2+ levels and time-dependent kinetics were continuously changing. Setting intracellular [Ca2+] ([Ca2+]i) to a known fixed value by using a Ca2+ chelating agent such AZD8055 in vitro as EGTA or BAPTA in the pipette solution allowed for studying Ca2+-activated Cl? currents (ICl(Ca)) under well-controlled conditions, such that time-dependent gating mechanisms could be investigated in detail under voltage-clamp conditions.7,16-18 Figure 1A shows a typical family of ICl(Ca) recorded in a rabbit PASMC dialyzed with a Cs+-containing pipette solution consisting of 10 mM BAPTA and 7.3 mM CaCl2 to clamp [Ca2+]i to 500 nM free Ca2+, with free [Mg2+] set to 1 mM. The elicited current reversed near Anticancer Compound Library the expected equilibrium potential for Cl? of ?0 mV (Fig. 1B) under the conditions of this experiment and displayed pronounced outward rectification (Fig. 1B), meaning that the underlying open channels carried more current in the outward direction (>0 mV; Cl? influx) than in the inward direction (