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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on March 13, 2006; DOI: 10.1124/jpet.105.098996

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Received for publication December 1, 2005.
Revised March 9, 2006.
Accepted for publication March 9, 2006.

Involvement of GRK3 and GRK2 in Down-regulation of the {alpha}2B-Adrenoceptor

Aarti N. Desai 1, Samina Salim 1, Kelly M. Standifer 1, Douglas C. Eikenburg 1*

1 University of Houston

* Address correspondence to: E-mail: deikenburg{at}uh.edu

Abstract

Increasing the cellular levels of GRK2 or GRK3 renders the {alpha}2B-AR more sensitive to agonist-induced down-regulation (Desai et al., 2004). However, an absolute requirement of GRK3 and GRK2 for {alpha}2B-AR down-regulation is controversial. In this study, using NG108 cells (endogenous {alpha}2B-AR), we provide strong evidence for a critical role of both GRK3 and GRK2 in down-regulation of the {alpha}2B-AR. Pretreatment of NG108 cells with 20 µM EPI begins down-regulating the {alpha}2B-AR by 2 h. The translocation of GRK3 and GRK2 to the membrane peaks at 30 min; decreasing by 1h. While these results may implicate GRK3 and GRK2 in {alpha}2B-AR down-regulation, significant receptor down-regulation is not observed until 2 h, after GRK3 and GRK2 translocation has peaked and is declining. To more directly establish a role for GRK3 and GRK2 in {alpha}2B-AR down-regulation, NG108 cells were transfected to express GRK3ct, which binds to liberated G{beta}{gamma} subunits, preventing GRK3 and GRK2 translocation to the membrane. Over-expression of GRK3ct prevented not only the translocation of GRK3 and GRK2, but also the down-regulation of the {alpha}2B-AR caused by 24 h pretreatment with 20 µM EPI. Taken together, these data provide direct evidence for a role of GRK3 and GRK2 in the down-regulation of the {alpha}2B-AR and contribute significantly to the increasing evidence in the literature for a pivotal role of GRKs in modulating the agonist-induced down-regulation of the {alpha}2-AR.


Key words: GRK2, GRK3, GRK3ct, alpha2-adrenoceptor, desensitization, down-regulation


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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]


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