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S-Palmitoylation of a Novel Site in the β2-Adrenergic Receptor Associated with a Novel Intracellular Itinerary.

Publication ,  Journal Article
Adachi, N; Hess, DT; McLaughlin, P; Stamler, JS
Published in: The Journal of biological chemistry
September 2016

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.

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Published In

The Journal of biological chemistry

DOI

EISSN

1083-351X

ISSN

0021-9258

Publication Date

September 2016

Volume

291

Issue

38

Start / End Page

20232 / 20246

Related Subject Headings

  • Thiolester Hydrolases
  • Receptors, Adrenergic, beta-2
  • Protein Transport
  • Protein Processing, Post-Translational
  • Lipoylation
  • Humans
  • HEK293 Cells
  • Golgi Apparatus
  • Cyclic AMP
  • Biochemistry & Molecular Biology
 

Citation

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Adachi, N., Hess, D. T., McLaughlin, P., & Stamler, J. S. (2016). S-Palmitoylation of a Novel Site in the β2-Adrenergic Receptor Associated with a Novel Intracellular Itinerary. The Journal of Biological Chemistry, 291(38), 20232–20246. https://doi.org/10.1074/jbc.m116.725762
Adachi, Naoko, Douglas T. Hess, Precious McLaughlin, and Jonathan S. Stamler. “S-Palmitoylation of a Novel Site in the β2-Adrenergic Receptor Associated with a Novel Intracellular Itinerary.The Journal of Biological Chemistry 291, no. 38 (September 2016): 20232–46. https://doi.org/10.1074/jbc.m116.725762.
Adachi N, Hess DT, McLaughlin P, Stamler JS. S-Palmitoylation of a Novel Site in the β2-Adrenergic Receptor Associated with a Novel Intracellular Itinerary. The Journal of biological chemistry. 2016 Sep;291(38):20232–46.
Adachi, Naoko, et al. “S-Palmitoylation of a Novel Site in the β2-Adrenergic Receptor Associated with a Novel Intracellular Itinerary.The Journal of Biological Chemistry, vol. 291, no. 38, Sept. 2016, pp. 20232–46. Epmc, doi:10.1074/jbc.m116.725762.
Adachi N, Hess DT, McLaughlin P, Stamler JS. S-Palmitoylation of a Novel Site in the β2-Adrenergic Receptor Associated with a Novel Intracellular Itinerary. The Journal of biological chemistry. 2016 Sep;291(38):20232–20246.

Published In

The Journal of biological chemistry

DOI

EISSN

1083-351X

ISSN

0021-9258

Publication Date

September 2016

Volume

291

Issue

38

Start / End Page

20232 / 20246

Related Subject Headings

  • Thiolester Hydrolases
  • Receptors, Adrenergic, beta-2
  • Protein Transport
  • Protein Processing, Post-Translational
  • Lipoylation
  • Humans
  • HEK293 Cells
  • Golgi Apparatus
  • Cyclic AMP
  • Biochemistry & Molecular Biology