title: The Protein Acyl Transferase ZDHHC21 Modulates α1 Adrenergic Receptor Function and Regulates Hemodynamics.
abstract: OBJECTIVE
  Palmitoylation, the reversible addition of the lipid palmitate to a cysteine, can alter protein localization, stability, and function. The ZDHHC family of protein acyl transferases catalyzes palmitoylation of numerous proteins. The role of ZDHHC enzymes in intact tissue and in vivo is largely unknown. Herein, we characterize vascular functions in a mouse that expresses a nonfunctional ZDHHC21 (F233Δ).
  
  
  RESULTS
  Physiological studies of isolated aortae and mesenteric arteries from F233Δ mice revealed an unexpected defect in responsiveness to phenylephrine, an α1 adrenergic receptor agonist. In vivo, F233Δ mice displayed a blunted response to infusion of phenylephrine, and they were found to have elevated catecholamine levels and elevated vascular α1 adrenergic receptor gene expression. Telemetry studies showed that the F233Δ mice were tachycardic and hypotensive at baseline, consistent with diminished vascular tone. In biochemical studies, ZDHHC21 was shown to palmitoylate the α1D adrenoceptor and to interact with it in a molecular complex, thus suggesting a possible molecular mechanism by which the receptor can be regulated by ZDHHC21.
  
  
  CONCLUSIONS
  Together, the data support a model in which ZDHHC21 F233Δ diminishes the function of vascular α1 adrenergic receptors, leading to reduced vascular tone, which manifests in vivo as hypotension and tachycardia. This is to our knowledge the first demonstration of a ZDHHC isoform affecting vascular function in vivo and identifies a novel molecular mode of regulation of vascular tone and blood pressure.
authors.affiliation: From the Section of Nephrology (E.P.M., L.J., J.M., H.V.) and Department of Dermatology (L.M.M.), Yale School of Medicine, New Haven, CT; and Vascular Biology and Therapeutics Program, Department of Pharmacology, Yale University School of Medicine, New Haven, CT (A.D.L., K.F.H., A.K.L., W.C.S.). ethan.marin@yale.edu.
authors.forename: Ethan P
authors.initials: EP
authors.lastname: Marin
authors.affiliation: From the Section of Nephrology (E.P.M., L.J., J.M., H.V.) and Department of Dermatology (L.M.M.), Yale School of Medicine, New Haven, CT; and Vascular Biology and Therapeutics Program, Department of Pharmacology, Yale University School of Medicine, New Haven, CT (A.D.L., K.F.H., A.K.L., W.C.S.).
authors.forename: Levente
authors.initials: L
authors.lastname: Jozsef
authors.affiliation: From the Section of Nephrology (E.P.M., L.J., J.M., H.V.) and Department of Dermatology (L.M.M.), Yale School of Medicine, New Haven, CT; and Vascular Biology and Therapeutics Program, Department of Pharmacology, Yale University School of Medicine, New Haven, CT (A.D.L., K.F.H., A.K.L., W.C.S.).
authors.forename: Annarita
authors.initials: A
authors.lastname: Di Lorenzo
authors.affiliation: From the Section of Nephrology (E.P.M., L.J., J.M., H.V.) and Department of Dermatology (L.M.M.), Yale School of Medicine, New Haven, CT; and Vascular Biology and Therapeutics Program, Department of Pharmacology, Yale University School of Medicine, New Haven, CT (A.D.L., K.F.H., A.K.L., W.C.S.).
authors.forename: Kara F
authors.initials: KF
authors.lastname: Held
authors.affiliation: From the Section of Nephrology (E.P.M., L.J., J.M., H.V.) and Department of Dermatology (L.M.M.), Yale School of Medicine, New Haven, CT; and Vascular Biology and Therapeutics Program, Department of Pharmacology, Yale University School of Medicine, New Haven, CT (A.D.L., K.F.H., A.K.L., W.C.S.).
authors.forename: Amelia K
authors.initials: AK
authors.lastname: Luciano
authors.affiliation: From the Section of Nephrology (E.P.M., L.J., J.M., H.V.) and Department of Dermatology (L.M.M.), Yale School of Medicine, New Haven, CT; and Vascular Biology and Therapeutics Program, Department of Pharmacology, Yale University School of Medicine, New Haven, CT (A.D.L., K.F.H., A.K.L., W.C.S.).
authors.forename: Jonathan
authors.initials: J
authors.lastname: Melendez
authors.affiliation: From the Section of Nephrology (E.P.M., L.J., J.M., H.V.) and Department of Dermatology (L.M.M.), Yale School of Medicine, New Haven, CT; and Vascular Biology and Therapeutics Program, Department of Pharmacology, Yale University School of Medicine, New Haven, CT (A.D.L., K.F.H., A.K.L., W.C.S.).
authors.forename: Leonard M
authors.initials: LM
authors.lastname: Milstone
authors.affiliation: From the Section of Nephrology (E.P.M., L.J., J.M., H.V.) and Department of Dermatology (L.M.M.), Yale School of Medicine, New Haven, CT; and Vascular Biology and Therapeutics Program, Department of Pharmacology, Yale University School of Medicine, New Haven, CT (A.D.L., K.F.H., A.K.L., W.C.S.).
authors.forename: Heino
authors.initials: H
authors.lastname: Velazquez
authors.affiliation: From the Section of Nephrology (E.P.M., L.J., J.M., H.V.) and Department of Dermatology (L.M.M.), Yale School of Medicine, New Haven, CT; and Vascular Biology and Therapeutics Program, Department of Pharmacology, Yale University School of Medicine, New Haven, CT (A.D.L., K.F.H., A.K.L., W.C.S.).
authors.forename: William C
authors.initials: WC
authors.lastname: Sessa
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism*; D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D001794:Blood Pressure; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D005838:Genotype; D057809:HEK293 Cells; D006339:Heart Rate; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007022:Hypotension / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D054878:Lipoylation; D008638:Mesenteric Arteries / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D009638:Norepinephrine / Q000378:metabolism; D010641:Phenotype; D010656:Phenylephrine / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013610:Tachycardia / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D013997:Time Factors; D014162:Transfection; D014661:Vasoconstriction
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D018340:Receptors, Adrenergic, alpha-1; D010656:Phenylephrine; D000217:Acyltransferases; C548447:Zdhhc21 protein, mouse; D009638:Norepinephrine; D004837:Epinephrine
keywords: adrenergic agonists; blood pressure; catecholamines; palmitate; tachycardia