Genetic deficit of K Ca 3.1 channels protects against pulmonary circulatory collapse induced by TRPV4 channel activation

• Published in: British journal of pharmacology 2015-09, Vol.172 (18), p.4493
• Main Authors: Wandall-Frostholm, Christine, Dalsgaard, Thomas, Bajoriūnas, Vytis, Oliván-Viguera, Aida, Sadda, Veeruanjaneyulu, Beck, Lilliana, Mogensen, Susie, Stankevicius, Edgaras, Simonsen, Ulf, Köhler, Ralf
• Format: Article
• Language: English
• ISSN: 1476-5381

The intermediate conductance calcium/calmodulin-regulated K channel K 3.1 produces hyperpolarizing K currents that counteract depolarizing currents carried by transient receptor potential (TRP) channels, and provide the electrochemical driving force for Cl and fluid movements. We investigated whether a deficiency in K 3.1 (K 3.1 ) protects against fatal pulmonary circulatory collapse in mice after pharmacological activation of the calcium-permeable TRP subfamily vanilloid type 4 (TRPV4) channels. An opener of TRPV4 channels, GSK1016790A, was infused in wild-type (wt) and K 3.1 mice; haemodynamic parameters, histology and pulmonary vascular reactivity were measured; and patch clamp was performed on pulmonary arterial endothelial cells (PAEC). In wt mice, GSK1016790A decreased right ventricular and systemic pressure leading to a fatal circulatory collapse that was accompanied by increased protein permeability, lung haemorrhage and fluid extravasation. In contrast, K 3.1 mice exhibited a significantly smaller drop in pressure to GSK1016790A infusion, no haemorrhage and fluid water extravasation, and the mice survived. Moreover, the GSK1016790A-induced relaxation of pulmonary arteries of K 3.1 mice was significantly less than that of wt mice. GSK1016790A induced TRPV4 currents in PAEC from wt and K 3.1 mice, which co-activated K 3.1 and disrupted membrane resistance in wt PAEC, but not in K 3.1 PAEC. Our findings show that a genetic deficiency of K 3.1 channels prevented fatal pulmonary circulatory collapse and reduced lung damage caused by pharmacological activation of calcium-permeable TRPV4 channels. Therefore, inhibition of K 3.1channels may have therapeutic potential in conditions characterized by abnormal high endothelial calcium signalling, barrier disruption, lung oedema and pulmonary circulatory collapse.