title: S-Palmitoylation of a Novel Site in the β2-Adrenergic Receptor Associated with a Novel Intracellular Itinerary.
abstract: We report here that a population of human β2-adrenergic receptors (β2AR), a canonical G protein-coupled receptor, traffics along a previously undescribed intracellular itinerary via the Golgi complex that is associated with the sequential S-palmitoylation and depalmitoylation of a previously undescribed site of modification, Cys-265 within the third intracellular loop. Basal S-palmitoylation of Cys-265 is negligible, but agonist-induced β2AR activation results in enhanced S-palmitoylation, which requires phosphorylation by the cAMP-dependent protein kinase of Ser-261/Ser-262. Agonist-induced turnover of palmitate occurs predominantly on Cys-265. Cys-265 S-palmitoylation is mediated by the Golgi-resident palmitoyl transferases zDHHC9/14/18 and is followed by depalmitoylation by the plasma membrane-localized acyl-protein thioesterase APT1. Inhibition of depalmitoylation reveals that S-palmitoylation of Cys-265 may stabilize the receptor at the plasma membrane. In addition, β2AR S-palmitoylated at Cys-265 are selectively preserved under a sustained adrenergic stimulation, which results in the down-regulation and degradation of βAR. Cys-265 is not conserved in β1AR, and S-palmitoylation of Cys-265 may thus be associated with functional differences between β2AR and β1AR, including relative resistance of β2AR to down-regulation in multiple pathophysiologies. Trafficking via the Golgi complex may underlie new roles in G protein-coupled receptor biology.
authors.affiliation: From the Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio 44106, the Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, and.
authors.forename: Naoko
authors.initials: N
authors.lastname: Adachi
authors.affiliation: From the Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio 44106, the Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, and.
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Hess
authors.affiliation: From the Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio 44106, the Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, and.
authors.forename: Precious
authors.initials: P
authors.lastname: McLaughlin
authors.affiliation: From the Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio 44106, the Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, and the Harrington Discovery Institute, University Hospitals Case Medical Center, Cleveland, Ohio 44106 jonathan.stamler@case.edu.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Stamler
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D054878:Lipoylation / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism*; D013869:Thiolester Hydrolases / Q000378:metabolism
chemical_list: D018343:Receptors, Adrenergic, beta-2; D000242:Cyclic AMP; D000217:Acyltransferases; C557245:ZDHHC14 protein, human; C504825:ZDHHC9 protein, human; C402226:LYPLA1 protein, human; D013869:Thiolester Hydrolases
keywords: G protein-coupled receptor (GPCR); adrenergic receptor; membrane trafficking; protein palmitoylation; receptor desensitization