title: Functional assembly of Kv7.1/Kv7.5 channels with emerging properties on vascular muscle physiology.
abstract: OBJECTIVE
  Voltage-dependent K(+) (Kv) channels from the Kv7 family are expressed in blood vessels and contribute to cardiovascular physiology. Although Kv7 channel blockers trigger muscle contractions, Kv7 activators act as vasorelaxants. Kv7.1 and Kv7.5 are expressed in many vessels. Kv7.1 is under intense investigation because Kv7.1 blockers fail to modulate smooth muscle reactivity. In this study, we analyzed whether Kv7.1 and Kv7.5 may form functional heterotetrameric channels increasing the channel diversity in vascular smooth muscles.
  
  
  RESULTS
  Kv7.1 and Kv7.5 currents elicited in arterial myocytes, oocyte, and mammalian expression systems suggest the formation of heterotetrameric complexes. Kv7.1/Kv7.5 heteromers, exhibiting different pharmacological characteristics, participate in the arterial tone. Kv7.1/Kv7.5 associations were confirmed by coimmunoprecipitation, fluorescence resonance energy transfer, and fluorescence recovery after photobleaching experiments. Kv7.1/Kv7.5 heterotetramers were highly retained at the endoplasmic reticulum. Studies in HEK-293 cells, heart, brain, and smooth and skeletal muscles demonstrated that the predominant presence of Kv7.5 stimulates release of Kv7.1/Kv7.5 oligomers out of lipid raft microdomains. Electrophysiological studies supported that KCNE1 and KCNE3 regulatory subunits further increased the channel diversity. Finally, the analysis of rat isolated myocytes and human blood vessels demonstrated that Kv7.1 and Kv7.5 exhibited a differential expression, which may lead to channel diversity.
  
  
  CONCLUSIONS
  Kv7.1 and Kv7.5 form heterotetrameric channels increasing the diversity of structures which fine-tune blood vessel reactivity. Because the lipid raft localization of ion channels is crucial for cardiovascular physiology, Kv7.1/Kv7.5 heteromers provide efficient spatial and temporal regulation of smooth muscle function. Our results shed light on the debate about the contribution of Kv7 channels to vasoconstriction and hypertension.
authors.affiliation: From the Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain (A.O., M.R.-F., L.S., N.C., A.F.); Unidad de Biofísica, CSIC-UPV/EHU, Universidad del País Vasco, País Vasco, Spain (M.R.-F., A.E., A.V.); Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-Universidad Autónoma de Madrid, Madrid, Spain (A.d.l.C., A.P., C.V.); Departament de Patologia i Terapèutica Experimental, Hospital Universitari de Bellvitge-Universitat de Barcelona, Barcelona, Spain (J.M., E.C., C.S.); and Departamento de Farmacología, Universidad Complutense de Madrid, Ciber Enfermedades Respiratorias (CibeRes), Madrid, Spain (A.C., D.M.-C.).
authors.forename: Anna
authors.initials: A
authors.lastname: Oliveras
authors.affiliation: From the Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain (A.O., M.R.-F., L.S., N.C., A.F.); Unidad de Biofísica, CSIC-UPV/EHU, Universidad del País Vasco, País Vasco, Spain (M.R.-F., A.E., A.V.); Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-Universidad Autónoma de Madrid, Madrid, Spain (A.d.l.C., A.P., C.V.); Departament de Patologia i Terapèutica Experimental, Hospital Universitari de Bellvitge-Universitat de Barcelona, Barcelona, Spain (J.M., E.C., C.S.); and Departamento de Farmacología, Universidad Complutense de Madrid, Ciber Enfermedades Respiratorias (CibeRes), Madrid, Spain (A.C., D.M.-C.).
authors.forename: Meritxell
authors.initials: M
authors.lastname: Roura-Ferrer
authors.affiliation: From the Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain (A.O., M.R.-F., L.S., N.C., A.F.); Unidad de Biofísica, CSIC-UPV/EHU, Universidad del País Vasco, País Vasco, Spain (M.R.-F., A.E., A.V.); Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-Universidad Autónoma de Madrid, Madrid, Spain (A.d.l.C., A.P., C.V.); Departament de Patologia i Terapèutica Experimental, Hospital Universitari de Bellvitge-Universitat de Barcelona, Barcelona, Spain (J.M., E.C., C.S.); and Departamento de Farmacología, Universidad Complutense de Madrid, Ciber Enfermedades Respiratorias (CibeRes), Madrid, Spain (A.C., D.M.-C.).
authors.forename: Laura
authors.initials: L
authors.lastname: Solé
authors.affiliation: From the Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain (A.O., M.R.-F., L.S., N.C., A.F.); Unidad de Biofísica, CSIC-UPV/EHU, Universidad del País Vasco, País Vasco, Spain (M.R.-F., A.E., A.V.); Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-Universidad Autónoma de Madrid, Madrid, Spain (A.d.l.C., A.P., C.V.); Departament de Patologia i Terapèutica Experimental, Hospital Universitari de Bellvitge-Universitat de Barcelona, Barcelona, Spain (J.M., E.C., C.S.); and Departamento de Farmacología, Universidad Complutense de Madrid, Ciber Enfermedades Respiratorias (CibeRes), Madrid, Spain (A.C., D.M.-C.).
authors.forename: Alicia
authors.initials: A
authors.lastname: de la Cruz
authors.affiliation: From the Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain (A.O., M.R.-F., L.S., N.C., A.F.); Unidad de Biofísica, CSIC-UPV/EHU, Universidad del País Vasco, País Vasco, Spain (M.R.-F., A.E., A.V.); Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-Universidad Autónoma de Madrid, Madrid, Spain (A.d.l.C., A.P., C.V.); Departament de Patologia i Terapèutica Experimental, Hospital Universitari de Bellvitge-Universitat de Barcelona, Barcelona, Spain (J.M., E.C., C.S.); and Departamento de Farmacología, Universidad Complutense de Madrid, Ciber Enfermedades Respiratorias (CibeRes), Madrid, Spain (A.C., D.M.-C.).
authors.forename: Angela
authors.initials: A
authors.lastname: Prieto
authors.affiliation: From the Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain (A.O., M.R.-F., L.S., N.C., A.F.); Unidad de Biofísica, CSIC-UPV/EHU, Universidad del País Vasco, País Vasco, Spain (M.R.-F., A.E., A.V.); Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-Universidad Autónoma de Madrid, Madrid, Spain (A.d.l.C., A.P., C.V.); Departament de Patologia i Terapèutica Experimental, Hospital Universitari de Bellvitge-Universitat de Barcelona, Barcelona, Spain (J.M., E.C., C.S.); and Departamento de Farmacología, Universidad Complutense de Madrid, Ciber Enfermedades Respiratorias (CibeRes), Madrid, Spain (A.C., D.M.-C.).
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Etxebarria
authors.affiliation: From the Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain (A.O., M.R.-F., L.S., N.C., A.F.); Unidad de Biofísica, CSIC-UPV/EHU, Universidad del País Vasco, País Vasco, Spain (M.R.-F., A.E., A.V.); Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-Universidad Autónoma de Madrid, Madrid, Spain (A.d.l.C., A.P., C.V.); Departament de Patologia i Terapèutica Experimental, Hospital Universitari de Bellvitge-Universitat de Barcelona, Barcelona, Spain (J.M., E.C., C.S.); and Departamento de Farmacología, Universidad Complutense de Madrid, Ciber Enfermedades Respiratorias (CibeRes), Madrid, Spain (A.C., D.M.-C.).
authors.forename: Joan
authors.initials: J
authors.lastname: Manils
authors.affiliation: From the Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain (A.O., M.R.-F., L.S., N.C., A.F.); Unidad de Biofísica, CSIC-UPV/EHU, Universidad del País Vasco, País Vasco, Spain (M.R.-F., A.E., A.V.); Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-Universidad Autónoma de Madrid, Madrid, Spain (A.d.l.C., A.P., C.V.); Departament de Patologia i Terapèutica Experimental, Hospital Universitari de Bellvitge-Universitat de Barcelona, Barcelona, Spain (J.M., E.C., C.S.); and Departamento de Farmacología, Universidad Complutense de Madrid, Ciber Enfermedades Respiratorias (CibeRes), Madrid, Spain (A.C., D.M.-C.).
authors.forename: Daniel
authors.initials: D
authors.lastname: Morales-Cano
authors.affiliation: From the Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain (A.O., M.R.-F., L.S., N.C., A.F.); Unidad de Biofísica, CSIC-UPV/EHU, Universidad del País Vasco, País Vasco, Spain (M.R.-F., A.E., A.V.); Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-Universidad Autónoma de Madrid, Madrid, Spain (A.d.l.C., A.P., C.V.); Departament de Patologia i Terapèutica Experimental, Hospital Universitari de Bellvitge-Universitat de Barcelona, Barcelona, Spain (J.M., E.C., C.S.); and Departamento de Farmacología, Universidad Complutense de Madrid, Ciber Enfermedades Respiratorias (CibeRes), Madrid, Spain (A.C., D.M.-C.).
authors.forename: Enric
authors.initials: E
authors.lastname: Condom
authors.affiliation: From the Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain (A.O., M.R.-F., L.S., N.C., A.F.); Unidad de Biofísica, CSIC-UPV/EHU, Universidad del País Vasco, País Vasco, Spain (M.R.-F., A.E., A.V.); Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-Universidad Autónoma de Madrid, Madrid, Spain (A.d.l.C., A.P., C.V.); Departament de Patologia i Terapèutica Experimental, Hospital Universitari de Bellvitge-Universitat de Barcelona, Barcelona, Spain (J.M., E.C., C.S.); and Departamento de Farmacología, Universidad Complutense de Madrid, Ciber Enfermedades Respiratorias (CibeRes), Madrid, Spain (A.C., D.M.-C.).
authors.forename: Concepció
authors.initials: C
authors.lastname: Soler
authors.affiliation: From the Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain (A.O., M.R.-F., L.S., N.C., A.F.); Unidad de Biofísica, CSIC-UPV/EHU, Universidad del País Vasco, País Vasco, Spain (M.R.-F., A.E., A.V.); Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-Universidad Autónoma de Madrid, Madrid, Spain (A.d.l.C., A.P., C.V.); Departament de Patologia i Terapèutica Experimental, Hospital Universitari de Bellvitge-Universitat de Barcelona, Barcelona, Spain (J.M., E.C., C.S.); and Departamento de Farmacología, Universidad Complutense de Madrid, Ciber Enfermedades Respiratorias (CibeRes), Madrid, Spain (A.C., D.M.-C.).
authors.forename: Angel
authors.initials: A
authors.lastname: Cogolludo
authors.affiliation: From the Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain (A.O., M.R.-F., L.S., N.C., A.F.); Unidad de Biofísica, CSIC-UPV/EHU, Universidad del País Vasco, País Vasco, Spain (M.R.-F., A.E., A.V.); Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-Universidad Autónoma de Madrid, Madrid, Spain (A.d.l.C., A.P., C.V.); Departament de Patologia i Terapèutica Experimental, Hospital Universitari de Bellvitge-Universitat de Barcelona, Barcelona, Spain (J.M., E.C., C.S.); and Departamento de Farmacología, Universidad Complutense de Madrid, Ciber Enfermedades Respiratorias (CibeRes), Madrid, Spain (A.C., D.M.-C.).
authors.forename: Carmen
authors.initials: C
authors.lastname: Valenzuela
authors.affiliation: From the Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain (A.O., M.R.-F., L.S., N.C., A.F.); Unidad de Biofísica, CSIC-UPV/EHU, Universidad del País Vasco, País Vasco, Spain (M.R.-F., A.E., A.V.); Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-Universidad Autónoma de Madrid, Madrid, Spain (A.d.l.C., A.P., C.V.); Departament de Patologia i Terapèutica Experimental, Hospital Universitari de Bellvitge-Universitat de Barcelona, Barcelona, Spain (J.M., E.C., C.S.); and Departamento de Farmacología, Universidad Complutense de Madrid, Ciber Enfermedades Respiratorias (CibeRes), Madrid, Spain (A.C., D.M.-C.).
authors.forename: Alvaro
authors.initials: A
authors.lastname: Villarroel
authors.affiliation: From the Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain (A.O., M.R.-F., L.S., N.C., A.F.); Unidad de Biofísica, CSIC-UPV/EHU, Universidad del País Vasco, País Vasco, Spain (M.R.-F., A.E., A.V.); Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-Universidad Autónoma de Madrid, Madrid, Spain (A.d.l.C., A.P., C.V.); Departament de Patologia i Terapèutica Experimental, Hospital Universitari de Bellvitge-Universitat de Barcelona, Barcelona, Spain (J.M., E.C., C.S.); and Departamento de Farmacología, Universidad Complutense de Madrid, Ciber Enfermedades Respiratorias (CibeRes), Madrid, Spain (A.C., D.M.-C.).
authors.forename: Núria
authors.initials: N
authors.lastname: Comes
authors.affiliation: From the Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain (A.O., M.R.-F., L.S., N.C., A.F.); Unidad de Biofísica, CSIC-UPV/EHU, Universidad del País Vasco, País Vasco, Spain (M.R.-F., A.E., A.V.); Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-Universidad Autónoma de Madrid, Madrid, Spain (A.d.l.C., A.P., C.V.); Departament de Patologia i Terapèutica Experimental, Hospital Universitari de Bellvitge-Universitat de Barcelona, Barcelona, Spain (J.M., E.C., C.S.); and Departamento de Farmacología, Universidad Complutense de Madrid, Ciber Enfermedades Respiratorias (CibeRes), Madrid, Spain (A.C., D.M.-C.). afelipe@ub.edu.
authors.forename: Antonio
authors.initials: A
authors.lastname: Felipe
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006801:Humans; D051656:KCNQ Potassium Channels / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051657:KCNQ1 Potassium Channel / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D021962:Membrane Microdomains / Q000378:metabolism; D008564:Membrane Potentials; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D051381:Rats; D014162:Transfection; D014981:Xenopus
chemical_list: D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; C412231:KCNQ5 protein, human; C496911:Kcnq1 protein, rat; C501028:Kcnq5 protein, rat; D011188:Potassium
keywords: KCNQ1 potassium channel; blood vessels; muscle; smooth