title: A molecular signature in the pannexin1 intracellular loop confers channel activation by the α1 adrenoreceptor in smooth muscle cells.
abstract: Both purinergic signaling through nucleotides such as ATP (adenosine 5'-triphosphate) and noradrenergic signaling through molecules such as norepinephrine regulate vascular tone and blood pressure. Pannexin1 (Panx1), which forms large-pore, ATP-releasing channels, is present in vascular smooth muscle cells in peripheral blood vessels and participates in noradrenergic responses. Using pharmacological approaches and mice conditionally lacking Panx1 in smooth muscle cells, we found that Panx1 contributed to vasoconstriction mediated by the α1 adrenoreceptor (α1AR), whereas vasoconstriction in response to serotonin or endothelin-1 was independent of Panx1. Analysis of the Panx1-deficient mice showed that Panx1 contributed to blood pressure regulation especially during the night cycle when sympathetic nervous activity is highest. Using mimetic peptides and site-directed mutagenesis, we identified a specific amino acid sequence in the Panx1 intracellular loop that is essential for activation by α1AR signaling. Collectively, these data describe a specific link between noradrenergic and purinergic signaling in blood pressure homeostasis.
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Billaud
authors.affiliation: Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Yu-Hsin
authors.initials: YH
authors.lastname: Chiu
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Lohman
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Thibaud
authors.initials: T
authors.lastname: Parpaite
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Butcher
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Mutchler
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Leon J
authors.initials: LJ
authors.lastname: DeLalio
authors.affiliation: Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Mykhaylo V
authors.initials: MV
authors.lastname: Artamonov
authors.affiliation: Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Joanna K
authors.initials: JK
authors.lastname: Sandilos
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Angela K
authors.initials: AK
authors.lastname: Best
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Avril V
authors.initials: AV
authors.lastname: Somlyo
authors.affiliation: Department of Cell Biology and Anatomy, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Thompson
authors.affiliation: Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Thu H
authors.initials: TH
authors.lastname: Le
authors.affiliation: Center for Cell Clearance, University of Virginia, Charlottesville, VA 22908, USA. Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA. Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Kodi S
authors.initials: KS
authors.lastname: Ravichandran
authors.affiliation: Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Bayliss
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. brant@virginia.edu.
authors.forename: Brant E
authors.initials: BE
authors.lastname: Isakson
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D015153:Blotting, Western; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D019332:Endothelin-1 / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013686:Telemetry; D014661:Vasoconstriction / Q000502:physiology*
chemical_list: D017630:Connexins; D019332:Endothelin-1; D009419:Nerve Tissue Proteins; C503631:Panx1 protein, mouse; D018340:Receptors, Adrenergic, alpha-1; D012701:Serotonin; D000255:Adenosine Triphosphate