title: Genetic deficit of KCa3.1 channels protects against pulmonary circulatory collapse induced by TRPV4 channel activation.
abstract: OBJECTIVE
  The intermediate conductance calcium/calmodulin-regulated K+channel KCa3.1 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 KCa3.1 (KCa3.1-/-) protects against fatal pulmonary circulatory collapse in mice after pharmacological activation of the calcium-permeable TRP subfamily vanilloid type 4 (TRPV4) channels.
  
  
  METHODS
  An opener of TRPV4 channels, GSK1016790A, was infused in wild-type (wt) and KCa3.1-/-mice; haemodynamic parameters, histology and pulmonary vascular reactivity were measured; and patch clamp was performed on pulmonary arterial endothelial cells (PAEC).
  
  
  RESULTS
  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, KCa3.1-/-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 KCa3.1-/-mice was significantly less than that of wt mice. GSK1016790A induced TRPV4 currents in PAEC from wt and KCa3.1-/-mice, which co-activated KCa3.1 and disrupted membrane resistance in wt PAEC, but not in KCa3.1-/-PAEC.
  
  
  CONCLUSIONS
  Our findings show that a genetic deficiency of KCa3.1 channels prevented fatal pulmonary circulatory collapse and reduced lung damage caused by pharmacological activation of calcium-permeable TRPV4 channels. Therefore, inhibition of KCa3.1channels may have therapeutic potential in conditions characterized by abnormal high endothelial calcium signalling, barrier disruption, lung oedema and pulmonary circulatory collapse.
authors.affiliation: Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark.
authors.forename: Christine
authors.initials: C
authors.lastname: Wandall-Frostholm
authors.affiliation: Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dalsgaard
authors.affiliation: Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark.|Department of Physiology and Pharmacology, Faculty of Medicine, Kaunas, Lithuania.
authors.forename: Vytis
authors.initials: V
authors.lastname: Bajoriūnas
authors.affiliation: Aragon Institute of Health Sciences IIS and ARAID, Zaragoza, Spain.
authors.forename: Aida
authors.initials: A
authors.lastname: Oliván-Viguera
authors.affiliation: Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark.
authors.forename: Veeruanjaneyulu
authors.initials: V
authors.lastname: Sadda
authors.affiliation: Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark.
authors.forename: Lilliana
authors.initials: L
authors.lastname: Beck
authors.affiliation: Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark.
authors.forename: Susie
authors.initials: S
authors.lastname: Mogensen
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Kaunas, Lithuania.
authors.forename: Edgaras
authors.initials: E
authors.lastname: Stankevicius
authors.affiliation: Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark.
authors.forename: Ulf
authors.initials: U
authors.lastname: Simonsen
authors.affiliation: Aragon Institute of Health Sciences IIS and ARAID, Zaragoza, Spain.
authors.forename: Ralf
authors.initials: R
authors.lastname: Köhler