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Desensitization of human CRF2(a) receptor signaling governed by agonist potency and ?arrestin2 recruitment.

ABSTRACT: The primary goal was to determine agonist-specific regulation of CRF2(a) receptor function. Exposure of human retinoblastoma Y79 cells to selective (UCN2, UCN3 or stresscopins) and non-selective (UCN1 or sauvagine) agonists prominently desensitized CRF2(a) receptors in a rapid, concentration-dependent manner. A considerably slower rate and smaller magnitude of desensitization developed in response to the weak agonist CRF. CRF1 receptor desensitization stimulated by CRF, cortagine or stressin1-A had no effect on CRF2(a) receptor cyclic AMP signaling. Conversely, desensitization of CRF2(a) receptors by UCN2 or UCN3 did not cross-desensitize Gs-coupled CRF1 receptor signaling. In transfected HEK293 cells, activation of CRF2(a) receptors by UCN2, UCN3 or CRF resulted in receptor phosphorylation and internalization proportional to agonist potency. Neither protein kinase A nor casein kinases mediated CRF2(a) receptor phosphorylation or desensitization. Exposure of HEK293 or U2OS cells to UCN2 or UCN3 (100nM) produced strong ?arrestin2 translocation and colocalization with membrane CRF2(a) receptors while CRF (1?M) generated only weak ?arrestin2 recruitment. ?arrestin2 did not internalize with the receptor, however, indicating that transient CRF2(a) receptor-arrestin complexes dissociate at or near the cell membrane. Since deletion of the ?arrestin2 gene upregulated Gs-coupled CRF2(a) receptor signaling in MEF cells, a ?arrestin2 mechanism restrains Gs-coupled CRF2(a) receptor signaling activated by urocortins. We further conclude that the rate and extent of homologous CRF2(a) receptor desensitization are governed by agonist-specific mechanisms affecting GRK phosphorylation, ?arrestin2 recruitment, and internalization thereby producing unique signal transduction profiles that differentially affect the stress response.

SUBMITTER: Hauger RL

PROVIDER: S-EPMC3924877 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Desensitization of human CRF2(a) receptor signaling governed by agonist potency and βarrestin2 recruitment.

Hauger Richard L RL Olivares-Reyes J Alberto JA Braun Sandra S Hernandez-Aranda Judith J Hudson Christine C CC Gutknecht Eric E Dautzenberg Frank M FM Oakley Robert H RH

Regulatory peptides 20130629

The primary goal was to determine agonist-specific regulation of CRF2(a) receptor function. Exposure of human retinoblastoma Y79 cells to selective (UCN2, UCN3 or stresscopins) and non-selective (UCN1 or sauvagine) agonists prominently desensitized CRF2(a) receptors in a rapid, concentration-dependent manner. A considerably slower rate and smaller magnitude of desensitization developed in response to the weak agonist CRF. CRF1 receptor desensitization stimulated by CRF, cortagine or stressin1-A ...[more]

PMID: 23820308

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Desensitization of human CRF2(a) receptor signaling governed by agonist potency and ?arrestin2 recruitment.

Publications

Desensitization of human CRF2(a) receptor signaling governed by agonist potency and βarrestin2 recruitment.

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