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CELLULAR AND MOLECULAR

Cellular G Protein-Coupled Receptor Kinase Levels Regulate Sensitivity of the _2B-Adrenergic Receptor to Undergo Agonist-Induced Down-Regulation

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

Chronic coactivation of _2B- and ₂-adrenoceptors (AR) was recently reported to down-regulate the _2B-AR at a lower threshold epinephrine (EPI) concentration compared with the activation of _2B-AR alone. This is the result of a modest ₂-AR-dependent up-regulation of G protein-coupled receptor kinase 3 (GRK3). In the present study, we determined that increasing GRK2 or GRK3 levels, independent of ₂-AR activation, decreases the EC₅₀ concentration for agonist-induced down-regulation of the _2B-AR using NG108 cells with or without overexpression (2- to 10-fold) of GRK2 or GRK3. In parental NG108 cells, the EC₅₀ concentration of EPI required for down-regulation of the _2B-AR is 30 µM. A 2- to 3-fold overexpression of GRK3 in NG108 cells, however, reduces the EC₅₀ to 0.2 µM (a 150-fold decrease), whereas a comparable overexpression of GRK2 reduces it to 1 µM (a 30-fold decrease). However, when GRK3 or GRK2 in NG108 cells are overexpressed 8- to 10-fold, the EC₅₀ concentration (0.02 µM EPI) for _2B-AR down-regulation is reduced 1000-fold. These data clearly suggest that a modest (2- to 3-fold) up-regulation of GRK3 is more effective at enhancing the sensitivity of _2B-AR to down-regulation after exposure to EPI than a modest up-regulation of GRK2, but that both GRK2 and GRK3 are equally effective at inducing _2B-AR down-regulation when up-regulated 8- to 10-fold. To our knowledge, this is the first report to systematically demonstrate that GRKs, particularly GRK3, play a pivotal role in modulating the agonist EC₅₀ concentration that down-regulates the _2B-AR and thus adds a new dimension to an already intricate signaling network.

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

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