title: Stromatoxin-sensitive, heteromultimeric Kv2.1/Kv9.3 channels contribute to myogenic control of cerebral arterial diameter.
abstract: Cerebral vascular smooth muscle contractility plays a crucial role in controlling arterial diameter and, thereby, blood flow regulation in the brain. A number of K(+) channels have been suggested to contribute to the regulation of diameter by controlling smooth muscle membrane potential (E(m)) and Ca(2+) influx. Previous studies indicate that stromatoxin (ScTx1)-sensitive, Kv2-containing channels contribute to the control of cerebral arterial diameter at 80 mmHg, but their precise role and molecular composition were not determined. Here, we tested if Kv2 subunits associate with 'silent' subunits from the Kv5, Kv6, Kv8 or Kv9 subfamilies to form heterotetrameric channels that contribute to control of diameter of rat middle cerebral arteries (RMCAs) over a range of intraluminal pressure from 10 to 100 mmHg. The predominant mRNAs expressed by RMCAs encode Kv2.1 and Kv9.3 subunits. Co-localization of Kv2.1 and Kv9.3 proteins at the plasma membrane of dissociated single RMCA myocytes was detected by proximity ligation assay. ScTx1-sensitive native current of RMCA myocytes and Kv2.1/Kv9.3 currents exhibited functional identity based on the similarity of their deactivation kinetics and voltage dependence of activation that were distinct from those of homomultimeric Kv2.1 channels. ScTx1 treatment enhanced the myogenic response of pressurized RMCAs between 40 and 100 mmHg, but this toxin also caused constriction between 10 and 40 mmHg that was not previously observed following inhibition of large conductance Ca(2+)-activated K(+) (BK(Ca)) and Kv1 channels. Taken together, this study defines the molecular basis of Kv2-containing channels and contributes to our understanding of the functional significance of their expression in cerebral vasculature. Specifically, our findings provide the first evidence of heteromultimeric Kv2.1/Kv9.3 channel expression in RMCA myocytes and their distinct contribution to control of cerebral arterial diameter over a wider range of E(m) and transmural pressure than Kv1 or BK(Ca) channels owing to their negative range of voltage-dependent activation.
authors.affiliation: The Smooth Muscle Research Group, Department of Physiology and Pharmacology, Faculty of Medicine, University of Calgary, 3330 Hospital Drive N.W., Calgary, Alberta, Canada T2N 4N1.
authors.forename: Xi Zoë
authors.initials: XZ
authors.lastname: Zhong
authors.forename: Khaled S
authors.initials: KS
authors.lastname: Abd-Elrahman
authors.forename: Chiu-Hsiang
authors.initials: CH
authors.lastname: Liao
authors.forename: Ahmed F
authors.initials: AF
authors.lastname: El-Yazbi
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Walsh
authors.forename: Michael P
authors.initials: MP
authors.lastname: Walsh
authors.forename: William C
authors.initials: WC
authors.lastname: Cole
mesh_terms: D000818:Animals; D002536:Cerebral Arteries / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D051659:KCNQ3 Potassium Channel / Q000737:chemistry / Q000502:physiology*; D008297:Male; D010455:Peptides / Q000502:physiology*; D055503:Protein Multimerization / Q000502:physiology*; D021122:Protein Subunits / Q000737:chemistry / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051669:Shab Potassium Channels / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D013111:Spider Venoms; D014661:Vasoconstriction / Q000502:physiology*
chemical_list: D051659:KCNQ3 Potassium Channel; C496991:Kcnb1 protein, rat; C496918:Kcnq3 protein, rat; D010455:Peptides; D021122:Protein Subunits; D051669:Shab Potassium Channels; D013111:Spider Venoms; C560803:stromatoxin protein, Stromatopelma calceata