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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

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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:
DateEvent
December 2006UNSPECIFIED
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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