title: Diminished hERG K+ channel activity facilitates strong human labour contractions but is dysregulated in obese women.
abstract: Human ether-a-go-go-related gene (hERG) potassium channels determine cardiac action potential and contraction duration. Human uterine contractions are underpinned by an action potential that also possesses an initial spike followed by prolonged depolarization. Here we show that hERG channel proteins (α-conducting and β-inhibitory subunits) and hERG currents exist in isolated patch-clamped human myometrial cells. We show that hERG channel activity suppresses contraction amplitude and duration before labour, thereby facilitating quiescence. During established labour, expression of β-inhibitory protein is markedly enhanced, resulting in reduced hERG activity that is associated with an increased duration of uterine action potentials and contractions. Thus, changes in hERG channel activity contribute to electrophysiological mechanisms that produce contractions during labour. We also demonstrate that this system fails in women with elevated BMI, who have enhanced hERG activity as a result of low β-inhibitory protein expression, which likely contributes to the weak contractions and poor labour outcomes observed in many obese women necessitating caesarean delivery.
authors.affiliation: Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Helena C
authors.initials: HC
authors.lastname: Parkington
authors.affiliation: Department of Perinatal Medicine Pregnancy Research Centre, Royal Women's Hospital, Parkville, Victoria 3052, Australia.
authors.forename: Janet
authors.initials: J
authors.lastname: Stevenson
authors.affiliation: Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Tonta
authors.affiliation: Mothers and Babies Research Centre, University of Newcastle, Callaghan, New South Wales 2308, Australia.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Paul
authors.affiliation: Mothers and Babies Research Centre, University of Newcastle, Callaghan, New South Wales 2308, Australia.
authors.forename: Trent
authors.initials: T
authors.lastname: Butler
authors.affiliation: Mothers and Babies Research Centre, University of Newcastle, Callaghan, New South Wales 2308, Australia.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Maiti
authors.affiliation: Mothers and Babies Research Centre, University of Newcastle, Callaghan, New South Wales 2308, Australia.
authors.forename: Eng-Cheng
authors.initials: EC
authors.lastname: Chan
authors.affiliation: Department of Perinatal Medicine Pregnancy Research Centre, Royal Women's Hospital, Parkville, Victoria 3052, Australia.
authors.forename: Penelope M
authors.initials: PM
authors.lastname: Sheehan
authors.affiliation: 1] Department of Perinatal Medicine Pregnancy Research Centre, Royal Women's Hospital, Parkville, Victoria 3052, Australia [2] Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Shaun P
authors.initials: SP
authors.lastname: Brennecke
authors.affiliation: Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Harold A
authors.initials: HA
authors.lastname: Coleman
authors.affiliation: Mothers and Babies Research Centre, University of Newcastle, Callaghan, New South Wales 2308, Australia.
authors.forename: Roger
authors.initials: R
authors.lastname: Smith
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000328:Adult; D015153:Blotting, Western; D015992:Body Mass Index; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D005260:Female; D006801:Humans; D008564:Membrane Potentials; D009215:Myometrium / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism; D018709:Statistics, Nonparametric; D014590:Uterine Contraction / Q000378:metabolism*
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; C489619:KCNE2 protein, human; C496884:KCNH1 protein, human; D024642:Potassium Channels, Voltage-Gated