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Differential responses of corticotropin-releasing hormone receptor type 1 variants to protein kinase C phosphorylation
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Markovic, Danijela, Papadopoulou, Nikolleta, Teli, Thalia, Randeva, Harpal S., Levine, Michael A., Hillhouse, Edward W. and Grammatopoulos, Dimitris (2006) Differential responses of corticotropin-releasing hormone receptor type 1 variants to protein kinase C phosphorylation. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 319 (3). pp. 1032-1042. doi:10.1124/jpet.106.107441
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Official URL: http://dx.doi.org/10.1124/jpet.106.107441
Abstract
Corticotropin-releasing hormone (CRH) regulates diverse biological functions in mammals, through activation of two types of specific G protein-coupled receptors that are expressed as multiple mRNA spliced variants. In most cells, the type 1 alpha CRH receptor (CRH-R1 alpha) preferentially activates the G(s)-adenylyl cyclase signaling cascade. CRH-R1 alpha-mediated signaling activity is impaired by insertion of 29 amino acids in the first intracellular loop, a sequence modification that is characteristic of the human-specific CRH-R1 beta variant. In various tissues, CRH signaling events are regulated by protein kinase C (PKC). The CRH receptors contain multiple putative PKC phosphorylation sites that represent potential targets. To investigate this, we expressed recombinant CRH-R1 alpha or CRH-R1 beta in human embryonic kidney 293 cells and analyzed signaling events after PKC activation. Agonist (oxytocin) or phorbol 12-myristate 13-acetate-induced activation of PKC led to phosphorylation of both CRH-R1 variants. However, CRH-R1 alpha and CRH-R1 beta exhibited different functional responses to PKC-induced phosphorylation, with only the CRH-R1 beta susceptible to cAMP signaling desensitization. This was associated with a significant decrease of accessible CRH-R1 beta receptors expressed on the cell surface. Both CRH-R1 variants were susceptible to homologous desensitization and internalization following treatment with CRH; however, PKC activation increased internalization of CRH-R1 beta but not CRH-R1 alpha in a beta-arrestin-independent manner. Our findings indicate that CRH-R1 alpha and -R1 beta exhibit differential responses to PKC-induced phosphorylation, and this might represent an important mechanism for functional regulation of CRH signaling in target cells.
| Item Type: | Journal Article | ||||
|---|---|---|---|---|---|
| Subjects: | R Medicine > RS Pharmacy and materia medica | ||||
| Journal or Publication Title: | JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS | ||||
| Publisher: | AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS | ||||
| ISSN: | 0022-3565 | ||||
| Official Date: | December 2006 | ||||
| Dates: |
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| Volume: | 319 | ||||
| Number: | 3 | ||||
| Number of Pages: | 11 | ||||
| Page Range: | pp. 1032-1042 | ||||
| DOI: | 10.1124/jpet.106.107441 | ||||
| Publication Status: | Published |
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