title: Contribution of kv7.4/kv7.5 heteromers to intrinsic and calcitonin gene-related peptide-induced cerebral reactivity.
abstract: OBJECTIVE
  Middle cerebral artery (MCA) diameter is regulated by inherent myogenic activity and the effect of potent vasodilators such as calcitonin gene-related peptide (CGRP). Previous studies showed that MCAs express KCNQ1, 4, and 5 potassium channel genes, and the expression products (Kv7 channels) participate in the myogenic control of MCA diameter. The present study investigated the contribution of Kv7.4 and Kv7.5 isoforms to myogenic and CGRP regulation of MCA diameter and determined whether they were affected in hypertensive animals.
  
  
  RESULTS
  Isometric tension recordings performed on MCA from normotensive rats produced CGRP vasodilations that were inhibited by the pan-Kv7 channel blocker linopirdine (P<0.01) and after transfection of arteries with siRNA against KCNQ4 (P<0.01) but not KCNQ5. However, isobaric myography revealed that myogenic constriction in response to increases in intravascular pressure (20-80 mm Hg) was affected by both KCNQ4 and KCNQ5 siRNA. Proximity ligation assay signals were equally abundant for Kv7.4/Kv7.4 or Kv7.4/Kv7.5 antibody combinations but minimal for Kv7.5/Kv7.5 antibodies or Kv7.4/7.1 combinations. In contrast to systemic arteries, Kv7 function and Kv7.4 abundance in MCA were not altered in hypertensive rats.
  
  
  CONCLUSIONS
  This study reveals, for the first time to our knowledge, that in cerebral arteries, Kv7.4 and Kv7.5 proteins exist predominantly as a functional heterotetramer, which regulates intrinsic myogenicity and vasodilation attributed to CGRP. Surprisingly, unlike systemic arteries, Kv7 activity in MCAs is not affected by the development of hypertension, and CGRP-mediated vasodilation is well maintained. As such, cerebrovascular Kv7 channels could be amenable for therapeutic targeting in conditions such as cerebral vasospasm.
authors.affiliation: From the Division of Biomedical Sciences, Pharmacology and Cell Physiology Research Group, St George's University of London, London, United Kingdom (P.S.C., T.A.J., G.C., J.B.S., I.A.G.); and The Smooth Muscle Research Group, Department of Physiology and Pharmacology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada (H.-L.Z., W.C.C.).
authors.forename: Preet S
authors.initials: PS
authors.lastname: Chadha
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Jepps
authors.forename: Georgina
authors.initials: G
authors.lastname: Carr
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Stott
authors.forename: Hei-Lei
authors.initials: HL
authors.lastname: Zhu
authors.forename: William C
authors.initials: WC
authors.lastname: Cole
authors.forename: Iain A
authors.initials: IA
authors.lastname: Greenwood
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology; D054086:KATP Channels / Q000378:metabolism; D051656:KCNQ Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D020768:Middle Cerebral Artery / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D020033:Protein Isoforms; D034622:RNA Interference; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D014162:Transfection; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D054086:KATP Channels; D051656:KCNQ Potassium Channels; C492166:Kcnq4 protein, rat; C501028:Kcnq5 protein, rat; D026902:Potassium Channel Blockers; D020033:Protein Isoforms; D014665:Vasodilator Agents; D015740:Calcitonin Gene-Related Peptide
keywords: KCNQ; Kv7; calcitonin gene-related peptide; cerebral arteries; rats, inbred SHR; vascular; vasodilation