Agonist-Mediated Destabilization of Human β1-adrenergic Receptor mRNA: Role of the 3′ Untranslated Translated Region

Abstract

For proto-oncogenes and cytokines, regulation of gene expression at the level of mRNA stability is well established. In contrast, there is comparatively limited knowledge regarding this mechanism of regulation for G-protein-coupled receptors. To explore this process further, the human β1-adrenergic receptor (AR) was stably expressed in tsAF8 cells. Treatment with β-agonist decreased the half-life of β1-AR mRNA by ∼50%. Removal of the 3′UTR from the β1-AR (coding region only) dramatically stabilized mRNA. Additionally, in a chimeric mRNA, the β1-AR 3′UTR was able to target the normally highly stable β-globin mRNA for accelerated decay. However, the chimera did not undergo agonist-mediated destabilization indicating that the 3′UTR may be “necessary but not sufficient” for agonist-mediated mRNA destabilization. Inhibition of translation significantly stabilized β1-AR mRNA (∼2-fold); however, pretreatment of cells with β-agonist prior to translational arrest produced the same degree of mRNA destabilization indicating that agonist-mediated destabilization may be independent of the translation process. Conversely, translational inhibition simultaneous with β-agonist exposure abrogated agonist-mediated destabilization indicating a dependence onde novoprotein synthesis.