title: TMEM16A/ANO1 channels contribute to the myogenic response in cerebral arteries.
abstract: BACKGROUND
  Pressure-induced arterial depolarization and constriction (the myogenic response) is a smooth muscle cell (myocyte)-specific mechanism that controls regional organ blood flow and systemic blood pressure. Several different nonselective cation channels contribute to pressure-induced depolarization, but signaling mechanisms involved are unclear. Similarly uncertain is the contribution of anion channels to the myogenic response and physiological functions and mechanisms of regulation of recently discovered transmembrane 16A (TMEM16A), also termed Anoctamin 1, chloride (Cl(-)) channels in arterial myocytes.
  
  
  OBJECTIVE
  To investigate the hypothesis that myocyte TMEM16A channels control membrane potential and contractility and contribute to the myogenic response in cerebral arteries.
  
  
  RESULTS
  Cell swelling induced by hyposmotic bath solution stimulated Cl(-) currents in arterial myocytes that were blocked by TMEM16A channel inhibitory antibodies, RNAi-mediated selective TMEM16A channel knockdown, removal of extracellular calcium (Ca(2+)), replacement of intracellular EGTA with BAPTA, a fast Ca(2+) chelator, and Gd(3+) and SKF-96365, nonselective cation channel blockers. In contrast, nimodipine, a voltage-dependent Ca(2+) channel inhibitor, or thapsigargin, which depletes intracellular Ca(2+) stores, did not alter swelling-activated TMEM16A currents. Pressure-induced (-40 mm Hg) membrane stretch activated ion channels in arterial myocyte cell-attached patches that were inhibited by TMEM16A antibodies and were of similar amplitude to recombinant TMEM16A channels. TMEM16A knockdown reduced intravascular pressure-induced depolarization and vasoconstriction but did not alter depolarization-induced (60 mmol/L K(+)) vasoconstriction.
  
  
  CONCLUSIONS
  Membrane stretch activates arterial myocyte TMEM16A channels, leading to membrane depolarization and vasoconstriction. Data also provide a mechanism by which a local Ca(2+) signal generated by nonselective cation channels stimulates TMEM16A channels to induce myogenic constriction.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Bulley
authors.forename: Zachary P
authors.initials: ZP
authors.lastname: Neeb
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Burris
authors.forename: John P
authors.initials: JP
authors.lastname: Bannister
authors.forename: Candice M
authors.initials: CM
authors.lastname: Thomas-Gatewood
authors.forename: Wanchana
authors.initials: W
authors.lastname: Jangsangthong
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Jaggar
mesh_terms: D000818:Animals; D000075369:Anoctamin-1; D001794:Blood Pressure / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002536:Cerebral Arteries / Q000166:cytology / Q000502:physiology*; D002560:Cerebrovascular Circulation / Q000502:physiology; D018118:Chloride Channels / Q000235:genetics / Q000502:physiology*; D002712:Chlorides / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000502:physiology*; D009553:Nimodipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D019284:Thapsigargin / Q000494:pharmacology; D014661:Vasoconstriction / Q000502:physiology
chemical_list: C552942:ANO1 protein, rat; D000075369:Anoctamin-1; D002121:Calcium Channel Blockers; D018118:Chloride Channels; D002712:Chlorides; D007093:Imidazoles; D034741:RNA, Small Interfering; D009553:Nimodipine; D019284:Thapsigargin; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole