Acute hypoxia selectively inhibits KCNA5 channels in pulmonary artery smooth muscle cells

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Abstract
Acute hypoxia causes pulmonary vasoconstriction in part by inhibiting voltage-gated K+ (Kv) channel activity in pulmonary artery smooth muscle cells (PASMC). The hypoxia-mediated decrease in Kv currents [IK(V)] is selective to PASMC; hypoxia has little effect on IK(V) in mesenteric artery smooth muscle cells (MASMC). Functional Kv channels are homo- and/or heterotetramers of pore-forming α-subunits and regulatory β-subunits. KCNA5 is a Kv channel α-subunit that forms functional Kv channels in PASMC and regulates resting membrane potential. We have shown that acute hypoxia selectively inhibits IK(V) through KCNA5 channels in PASMC. Overexpression of the human KCNA5 gene increased IK(V) and caused membrane hyperpolarization in HEK-293, COS-7, and rat MASMC and PASMC. Acute hypoxia did not affect IK(V) in KCNA5-transfected HEK-293 and COS-7 cells. However, overexpression of KCNA5 in PASMC conferred its sensitivity to hypoxia. Reduction of Po2 from 145 to 35 mmHg reduced IK(V) by ∼40% in rat PASMC transfected with human KCNA5 but had no effect on IK(V) in KCNA5-transfected rat MASMC (or HEK and COS cells). These results indicate that KCNA5 is an important Kv channel that regulates resting membrane potential and that acute hypoxia selectively reduces KCNA5 channel activity in PASMC relative to MASMC and other cell types. Because Kv channels (including KCNA5) are ubiquitously expressed in PASMC and MASMC, the observation from this study indicates that a hypoxia-sensitive mechanism essential for inhibiting KCNA5 channel activity is exclusively present in PASMC. The divergent effect of hypoxia on IK(V) in PASMC and MASMC also may be due to different expression levels of KCNA5 channels.