title: Drosophila KCNQ channel displays evolutionarily conserved electrophysiology and pharmacology with mammalian KCNQ channels.
abstract: Of the five human KCNQ (Kv7) channels, KCNQ1 with auxiliary subunit KCNE1 mediates the native cardiac I(Ks) current with mutations causing short and long QT cardiac arrhythmias. KCNQ4 mutations cause deafness. KCNQ2/3 channels form the native M-current controlling excitability of most neurons, with mutations causing benign neonatal febrile convulsions. Drosophila contains a single KCNQ (dKCNQ) that appears to serve alone the functions of all the duplicated mammalian neuronal and cardiac KCNQ channels sharing roughly 50-60% amino acid identity therefore offering a route to investigate these channels. Current information about the functional properties of dKCNQ is lacking therefore we have investigated these properties here. Using whole cell patch clamp electrophysiology we compare the biophysical and pharmacological properties of dKCNQ with the mammalian neuronal and cardiac KCNQ channels expressed in HEK cells. We show that Drosophila KCNQ (dKCNQ) is a slowly activating and slowly-deactivating K(+) current open at sub-threshold potentials that has similar properties to neuronal KCNQ2/3 with some features of the cardiac KCNQ1/KCNE1 accompanied by conserved sensitivity to a number of clinically relevant KCNQ blockers (chromanol 293B, XE991, linopirdine) and opener (zinc pyrithione). We also investigate the molecular basis of the differential selectivity of KCNQ channels to the opener retigabine and show a single amino acid substitution (M217W) can confer sensitivity to dKCNQ. We show dKCNQ has similar electrophysiological and pharmacological properties as the mammalian KCNQ channels, allowing future study of physiological and pathological roles of KCNQ in Drosophila and whole organism screening for new modulators of KCNQ channelopathies.
authors.affiliation: University of Bristol, School of Physiology and Pharmacology, Medical Sciences Building, Bristol, United Kingdom.
authors.forename: Sonia
authors.initials: S
authors.lastname: Cavaliere
authors.forename: James J L
authors.initials: JJ
authors.lastname: Hodge
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D002460:Cell Line; D002839:Chromans / Q000494:pharmacology; D004330:Drosophila; D029721:Drosophila Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004594:Electrophysiology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D051656:KCNQ Potassium Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051657:KCNQ1 Potassium Channel / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D051658:KCNQ2 Potassium Channel / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D051659:KCNQ3 Potassium Channel / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010655:Phenylenediamines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; D000873:Anthracenes; D002219:Carbamates; D002839:Chromans; D029721:Drosophila Proteins; D007211:Indoles; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D051658:KCNQ2 Potassium Channel; C496914:KCNQ2 protein, human; D051659:KCNQ3 Potassium Channel; C496916:KCNQ3 protein, human; C117367:KCNQ4 protein, human; D009942:Organometallic Compounds; D010655:Phenylenediamines; D011725:Pyridines; D013449:Sulfonamides; C101866:ezogabine; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane; C061017:linopirdine; C010423:pyrithione zinc