title: Kv7 Channel Activation Underpins EPAC-Dependent Relaxations of Rat Arteries.
abstract: To establish the role of Kv7 channels in EPAC (exchange protein directly activated by cAMP)-dependent relaxations of the rat vasculature and to investigate whether this contributes to β-adrenoceptor-mediated vasorelaxations.
  
  
  
  Isolated rat renal and mesenteric arteries (RA and MA, respectively) were used for isometric tension recording to study the relaxant effects of a specific EPAC activator and the β-adrenoceptor agonist isoproterenol in the presence of potassium channel inhibitors and cell signaling modulators. Isolated myocytes were used in proximity ligation assay studies to detect localization of signaling intermediaries with Kv7.4 before and after cell stimulation. Our studies showed that the EPAC activator (8-pCPT-2Me-cAMP-AM) produced relaxations and enhanced currents of MA and RA that were sensitive to linopirdine (Kv7 inhibitor). Linopirdine also inhibited isoproterenol-mediated relaxations in both RA and MA. In the MA, isoproterenol relaxations were sensitive to EPAC inhibition, but not protein kinase A inhibition. In contrast, isoproterenol relaxations in RA were attenuated by protein kinase A but not by EPAC inhibition. Proximity ligation assay showed a localization of Kv7.4 with A-kinase anchoring protein in both vessels in the basal state, which increased only in the RA with isoproterenol stimulation. In the MA, but not the RA, a localization of Kv7.4 with both Rap1a and Rap2 (downstream of EPAC) increased with isoproterenol stimulation.
  
  
  
  EPAC-dependent vasorelaxations occur in part via activation of Kv7 channels. This contributes to the isoproterenol-mediated relaxation in mesenteric, but not renal, arteries.
authors: From the Vascular Biology Research Group, Institute for Cardiovascular and Cell Sciences, St George's University of London, UK.
authors: Jennifer B
authors: JB
authors: Stott
authors: From the Vascular Biology Research Group, Institute for Cardiovascular and Cell Sciences, St George's University of London, UK.
authors: Vincenzo
authors: V
authors: Barrese
authors: From the Vascular Biology Research Group, Institute for Cardiovascular and Cell Sciences, St George's University of London, UK. grenwood@sgul.ac.uk.
authors: Iain A
authors: IA
authors: Greenwood
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020662:Guanine Nucleotide Exchange Factors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D051656:KCNQ Potassium Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017208:Rats, Wistar; D012077:Renal Artery / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D054758:A Kinase Anchor Proteins; D000318:Adrenergic beta-Agonists; D020662:Guanine Nucleotide Exchange Factors; D051656:KCNQ Potassium Channels; C492166:Kcnq4 protein, rat; D026902:Potassium Channel Blockers; D047428:Protein Kinase Inhibitors; C526973:Rapgef3 protein, rat; D014665:Vasodilator Agents; D017868:Cyclic AMP-Dependent Protein Kinases; D020827:rap1 GTP-Binding Proteins
keywords: K channel; cyclic nucleotide; isoproterenol; signaling pathways; vascular smooth muscle