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

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 [I(K(V))] is selective to PASMC; hypoxia has little effect on I(K(V)) in mesenteric artery smooth muscle cells (MASMC). Functional Kv channels are homo- and/or heterotetramers of pore-forming alpha-subunits and regulatory beta-subunits. KCNA5 is a Kv channel alpha-subunit that forms functional Kv channels in PASMC and regulates resting membrane potential. We have shown that acute hypoxia selectively inhibits I(K(V)) through KCNA5 channels in PASMC. Overexpression of the human KCNA5 gene increased I(K(V)) and caused membrane hyperpolarization in HEK-293, COS-7, and rat MASMC and PASMC. Acute hypoxia did not affect I(K(V)) in KCNA5-transfected HEK-293 and COS-7 cells. However, overexpression of KCNA5 in PASMC conferred its sensitivity to hypoxia. Reduction of Po(2) from 145 to 35 mmHg reduced I(K(V)) by approximately 40% in rat PASMC transfected with human KCNA5 but had no effect on I(K(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 I(K(V)) in PASMC and MASMC also may be due to different expression levels of KCNA5 channels.

Chronic hypoxia selectively enhances L- and T-type voltage-dependent Ca2+ channel activity in pulmonary artery by upregulating Cav1.2 and Cav3.2

“…Inhibition of K ϩ channels causes membrane depolarization, increases open probability of VDCC, promotes Ca 2ϩ influx, increases [Ca 2ϩ ] cyt , and triggers PASMC contraction. Our group and others have demonstrated that chronic hypoxia results in decreased expression and function of K v channels (11,39,41,42,53,54,61,62,65). In the present study, we show that, in addition to inhibiting K v channels, chronic hypoxia selectively enhances VDCC function and expression in PA and PASMC (but not in MA).…”

Hypoxia. 4. Hypoxia and ion channel function

“…Some studies suggested a prominent role for the K V 1.5 subunit (8, 73); however, this was countered by data from non-PASMC expression systems indicating that expression of either K V 1.5 or K V 1.2 resulted in currents that were insensitive to hypoxia (160,176) or only inhibited at very high E m (103). Interestingly, a hypoxiasensitive I K did develop when K V 1.2 and K V 1.5 were coexpressed (103, 160) or when K V 1.5 was expressed in PASMCs (176). These findings suggest that O 2 sensitivity may be determined by the host cell (41, 133).…”

Mitochondrial cytochrome redox states and respiration in acute pulmonary oxygen sensing

“…4b) allows for the conclusions that: 1) either inhibition of respiration is not the single mechanism underlying HPV; 2) that the difference in responses of PASMC and ASMC to hypoxia is caused by mechanisms downstream of a reduction in respiration, e.g. by different ion channel expression [31], or specific regulation of ion channel function [32]; or 3) with regard to ASMC, ASMC react similar to PASMC as they face rather high PO 2 in vivo with the aorta carrying well oxygenated blood. The latter explanation is supported by the fact that, in contrast to ASMC, RASMC showed no hypoxia-induced membrane hyperpolarisation, which corresponds to higher respiration in hypoxia.…”