JPET Introducing ALZET?ew Model 2006 Pump

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on September 6, 2006; DOI: 10.1124/jpet.106.107441

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jpet.106.107441v1
319/3/1032    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Markovic, D.
Right arrow Articles by Grammatopoulos, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Markovic, D.
Right arrow Articles by Grammatopoulos, D.


Received for publication May 12, 2006.
Revised August 31, 2006.
Accepted for publication August 31, 2006.

Differential responses of CRH receptor type 1 variants to PKC phosphorylation

Danijela Markovic 1, Nikoletta Papadopoulou 1, Thalia Teli 1, Harpal Randeva 1, Michael A. Levine 2, Edward W. Hillhouse 3, Dimitris Grammatopoulos 1*

1 Warwick Medical School 2 The Children's Hospital of The Cleveland Clinic Foundation 3 University of Leeds

* Address correspondence to: E-mail: d.grammatopoulos{at}warwick.ac.uk

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 Gs-adenylyl cyclase signalling cascade. CRH-R1{alpha}-mediated signalling activity is impaired by insertion of 29-amino acids in the 1st intracellular loop, a sequence modification that is characteristic of the human-specific CRH-R1{beta} variant. In various tissues, CRH signalling 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 HEK-293 cells and analyzed signalling events after PKC activation. Agonist (oxytocin) or PMA-induced activation of PKC led to phosphorylation of both CRH-R1 variants. However, CRH-R1{alpha} and CRHR1{beta} exhibited different functional responses to PKC-induced phosphorylation, with only the CRH-R1{beta} susceptible to cAMP signalling 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 signalling in target cells.


Key words: CRH-R1, PKC, desensitization, internalization, phosphorylation, receptor variants


This article has been cited by other articles:


Home page
 Mol. Endocrinol.Home page
D. Markovic, H. Lehnert, M. A. Levine, and D. K. Grammatopoulos
Structural Determinants Critical for Localization and Signaling within the Seventh Transmembrane Domain of the Type 1 Corticotropin Releasing Hormone Receptor: Lessons from the Receptor Variant R1d
Mol. Endocrinol., November 1, 2008; 22(11): 2505 - 2519.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
J. Tao, M. E. Hildebrand, P. Liao, M. C. Liang, G. Tan, S. Li, T. P. Snutch, and T. W. Soong
Activation of Corticotropin-Releasing Factor Receptor 1 Selectively Inhibits CaV3.2 T-Type Calcium Channels
Mol. Pharmacol., June 1, 2008; 73(6): 1596 - 1609.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
R. H. Oakley, J. A. Olivares-Reyes, C. C. Hudson, F. Flores-Vega, F. M. Dautzenberg, and R. L. Hauger
Carboxyl-terminal and intracellular loop sites for CRF1 receptor phosphorylation and beta-arrestin-2 recruitment: a mechanism regulating stress and anxiety responses
Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2007; 293(1): R209 - R222.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2006 by the American Society for Pharmacology and Experimental Therapeutics.