Ca2+‐Dependent Cl‐ Channel Activation by Store‐Operated Ca2+ Influx in Rabbit Pulmonary Artery Myocytes

Abstract

Numerous studies have shown that the Ca2+ activated Cl− current in vascular smooth muscle (ICl(Ca)) can be triggered by various sources of Ca2+ which include Ca2+ entry via either voltage-gated Ca2+ channels or reverse-mode Na+/ Ca2+ exchange and spontaneous or agonist-induced Ca2+ release from internal stores. We sought to explore the possibility that Ca2+ entry via store-operated non-selective cation channels (SOCs) can elicit ICl(Ca) in voltage clamped rabbit pulmonary arterial myocytes. Thapsigargin (THG) or cyclopiazonic acid (CPA) elicited a current reversing near 0 mV during an initial hyperpolarizing (HP) step, and an outward time-dependent ICl(Ca) at +90 mV followed by an ICl(Ca) tail at 80 mV. The magnitude of both outward and tail currents increased exponentially with membrane HP. Measuring intracellular calcium with Fluo4, CPA led to an initial Ca2+ transient followed by a sustained elevation of [Ca2+]i likely supported by Ca2+ entry through SOCs. During sustained phase Ca2+ elevation, application of KATP agonist levcromakalim (LEV) further increased [Ca2+]i. These results indicate that graded driving force-dependent Ca2+ entry via ISOC during HP steps or following exposure to LEV may activate ICl(Ca), and suggest a relationship between two important mechanisms regulating membrane potential and pulmonary arterial tone. [NHLBI: 1 RO1 HL075477-01-A2 (NL); COBRE: NCRR 5 P20 RR15581 (NL)]