QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.069674v1 311/2/794    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Desai, A. N. Articles by Eikenburg, D. C. Search for Related Content PubMed PubMed Citation Articles by Desai, A. N. Articles by Eikenburg, D. C.

CELLULAR AND MOLECULAR

Simultaneous _2B- and ₂-Adrenoceptor Activation Sensitizes the _2B-Adrenoceptor for Agonist-Induced Down-Regulation

Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas

We recently reported that _2A-adrenoceptor (AR) desensitization and down-regulation occurs after 24-h treatment with epinephrine (EPI) (0.3 µM) in BE(2)-C cells that express both ₂- and ₂-ARs. The same concentration of norepinephrine (NE) has no effect. The effect of EPI is prevented by ₂-AR blockade and is associated with an increase in G protein-coupled receptor kinase 3 (GRK3) expression. Because differences in agonist-induced down-regulation of the _2A-versus _2B-ARs have been reported, the present study examines the effects of simultaneous activation of _2B- and ₂-ARs on _2B-AR number and signaling. We studied NG108 cells that naturally express _2B-ARs, and BN17 cells, NG108 cells transfected to express the human ₂-AR. In NG108 cells, _2B-AR desensitization and down-regulation require treatment with 20 µM EPI or NE; GRK expression was not changed. In BN17 cells expressing ₂-ARs, the threshold EPI concentration for _2B-AR desensitization and down-regulation was reduced to 0.3 µM; 10 µM NE was required for the same effect. Furthermore, 24-h EPI or NE treatments that produced desensitization also resulted in a selective 2-fold up-regulation of GRK3; GRK2 was unchanged. The -AR antagonist alprenolol (1 µM) and GRK3 antisense (but not sense) DNA blocked 0.3 µM EPI- and 10 µM NE-induced desensitization and down-regulation of the _2B-AR as well as GRK3 up-regulation. In conclusion, simultaneous activation of _2B- and ₂-ARs results in a 67-fold decrease in the threshold concentration of EPI required for _2B-AR down-regulation. This lower threshold for down-regulation is associated with _2B- and ₂-AR dependent up-regulation of GRK3 expression.

Address correspondence to: Dr. Douglas C. Eikenburg, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204-5037. E-mail: deikenburg{at}uh.edu

This article has been cited by other articles:

				S. Salim, K. M. Standifer, and D. C. Eikenburg Extracellular Signal-Regulated Kinase 1/2-Mediated Transcriptional Regulation of G-Protein-Coupled Receptor Kinase 3 Expression in Neuronal Cells J. Pharmacol. Exp. Ther., April 1, 2007; 321(1): 51 - 59. [Abstract] [Full Text] [PDF]

				S. Salim and D. C. Eikenburg Role of 90-kDa Heat Shock Protein (Hsp 90) and Protein Degradation in Regulating Neuronal Levels of G Protein-Coupled Receptor Kinase 3 J. Pharmacol. Exp. Ther., March 1, 2007; 320(3): 1106 - 1112. [Abstract] [Full Text] [PDF]

				A. N. Desai, S. Salim, K. M. Standifer, and D. C. Eikenburg Involvement of G Protein-Coupled Receptor Kinase (GRK) 3 and GRK2 in Down-Regulation of the {alpha}2B-Adrenoceptor J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 1027 - 1035. [Abstract] [Full Text] [PDF]

				A. N. Desai, K. M. Standifer, and D. C. Eikenburg Cellular G Protein-Coupled Receptor Kinase Levels Regulate Sensitivity of the {alpha}2B-Adrenergic Receptor to Undergo Agonist-Induced Down-Regulation J. Pharmacol. Exp. Ther., February 1, 2005; 312(2): 767 - 773. [Abstract] [Full Text] [PDF]