title: Beta1-adrenergic receptor-mediated dilation of rat cerebral artery requires Shaker-type KV1 channels on PSD95 scaffold.
abstract: Postsynaptic density-95 (PSD95) is a scaffolding protein in cerebral vascular smooth muscle cells (cVSMCs), which binds to Shaker-type K(+) (KV1) channels and facilitates channel opening through phosphorylation by protein kinase A. β1-Adrenergic receptors (β1ARs) also have a binding motif for PSD95. Functional association of β1AR with KV1 channels through PSD95 may represent a novel vasodilator complex in cerebral arteries (CA). We explored whether a β1AR-PSD95-KV1 complex is a determinant of rat CA dilation. RT-PCR and western blots revealed expression of β1AR in CA. Isoproterenol induced a concentration-dependent dilation of isolated, pressurized rat CA that was blocked by the β1AR blocker CGP20712. Cranial window imaging of middle cerebral arterioles in situ showed isoproterenol- and norepinephrine-induced dilation that was blunted by β1AR blockade. Isoproterenol-induced hyperpolarization of cVSMCs in pressurized CA was blocked by CGP20712. Confocal images of cVSMCs immunostained with antibodies against β1AR and PSD95 indicated strong colocalization, and PSD95 co-immunoprecipitated with β1AR in CA lysate. Blockade of KV1 channels, β1AR or disruption of PSD95-KV1 interaction produced similar blunting of isoproterenol-induced dilation in pressurized CA. These findings suggest that PSD95 mediates a vasodilator complex with β1AR and KV1 channels in cVSMCs. This complex may be critical for proper vasodilation in rat CA.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Moore
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: McClenahan
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Hillary M
authors.initials: HM
authors.lastname: Hanvey
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Dae-Song
authors.initials: DS
authors.lastname: Jang
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Piper L
authors.initials: PL
authors.lastname: Nelson
authors.affiliation: Venenum Biodesign, Hamilton, New Jersey, USA.
authors.forename: Biny K
authors.initials: BK
authors.lastname: Joseph
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Sung W
authors.initials: SW
authors.lastname: Rhee
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002536:Cerebral Arteries / Q000502:physiology*; D000076122:Disks Large Homolog 4 Protein; D007093:Imidazoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*; D051637:Shaker Superfamily of Potassium Channels / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D000319:Adrenergic beta-Antagonists; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018342:Receptors, Adrenergic, beta-1; D051637:Shaker Superfamily of Potassium Channels; D014662:Vasoconstrictor Agents; C049763:CGP 20712A; D007545:Isoproterenol; D009638:Norepinephrine