Desensitization of the Y1 cell adrenocorticotropin receptor

Evidence for a restricted heterologous mechanism implying a role for receptor-effector complexes

Asma H. Baig, Francesca M. Swords, Luke A. Noon, Peter J. King, L. Hunyady, Adrian J L Clark

Research output: Contribution to journalArticle

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Abstract

Receptor desensitization provides a potential mechanism for the regulation of adrenocortical adrenocorticotropin (ACTH) responsiveness. Using the mouse adrenocortical Y1 cell line we demonstrate that ACTH effectively desensitizes the cAMP response of its own receptor, the melanocortin 2 receptor (MC2R), in these cells with a maximal effect between 30 and 60 min. Neither forskolin nor isoproterenol (in Y1 cells stably transfected with the β 2-adrenergic receptor) desensitize this ACTH response. ACTH desensitizes its receptor at concentrations at which only a fraction of receptors are occupied, implying that this mechanism acts on agonist-unoccupied receptors. Y1 cells express G protein-coupled receptor kinase (GRK) 2 and 5, but stable expression of a dominant negative GRK2 (K220W) only marginally reduces the desensitization by ACTH. The protein kinase A (PKA) inhibitor, H89, extinguishes almost the entire desensitization response over the initial 30-min period at all concentrations of ACTH. A mutant MC2R in which the single consensus PKA phosphorylation site has been mutated (S208A) when expressed in MC2R-negative Y6 cells is also unable to desensitize. These data imply a heterologous, PKA-dependent, mode of desensitization, which is restricted to agonist-occupied and -unoccupied MC2R, possibly as a consequence of receptor/effector complexes that functionally compartmentalize this receptor.

Original languageEnglish
Pages (from-to)44792-44797
Number of pages6
JournalJournal of Biological Chemistry
Volume276
Issue number48
DOIs
Publication statusPublished - Nov 30 2001

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Receptor, Melanocortin, Type 2
Adrenocorticotropic Hormone
Cyclic AMP-Dependent Protein Kinases
G-Protein-Coupled Receptor Kinase 5
G-Protein-Coupled Receptor Kinase 2
G-Protein-Coupled Receptor Kinases
Phosphorylation
Colforsin
Protein Kinase Inhibitors
Isoproterenol
Adrenergic Receptors
Cells
Cell Line

ASJC Scopus subject areas

  • Biochemistry

Cite this

Desensitization of the Y1 cell adrenocorticotropin receptor : Evidence for a restricted heterologous mechanism implying a role for receptor-effector complexes. / Baig, Asma H.; Swords, Francesca M.; Noon, Luke A.; King, Peter J.; Hunyady, L.; Clark, Adrian J L.

In: Journal of Biological Chemistry, Vol. 276, No. 48, 30.11.2001, p. 44792-44797.

Research output: Contribution to journalArticle

Baig, Asma H. ; Swords, Francesca M. ; Noon, Luke A. ; King, Peter J. ; Hunyady, L. ; Clark, Adrian J L. / Desensitization of the Y1 cell adrenocorticotropin receptor : Evidence for a restricted heterologous mechanism implying a role for receptor-effector complexes. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 48. pp. 44792-44797.
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