Adrenergic receptors (ARs) serve as important regulators of central nervous system- (CNS-) mediated behavior and several neural functions, including mood, memory, neuroendocrine control, and stimulation of autonomic function. Alterations in adrenergic receptor number have been implicated in the pathophysiology of affective psychiatric disorders, including depression. Beta-adrenergic receptor (beta-AR) down-regulation occurs during chronic treatment with antidepressants, suggesting that the dysregulation of the betal-adrenerqic receptor (beta1-AR) subtype, the predominant beta- AR subtype in the brain, may be associated with depressive illness. We propose to develop a mechanistic understanding of transcriptional and post-transcriptional beta1-AR mRNA control during antidepressant therapy. We have examined the molecular mechanisms underlying beta1-AR mRNA down-regulation following agonist induction, and have identified potential transcriptional and post-transcriptional control mechanisms. Firstly, we have recently determined that the RNA binding factors HuR, hnRNP A1, and AUF-1 all interact with the 3' untranslated region (UTR) of the rat 61- AR mRNAs, and that HuR becomes induced in the presence of beta-AR agonist isoproterenol, resulting in the acceleration of _I-AR transcript degradation. Secondly, we have determined that exposure of C6 cells to isoproterenol results in a rapid induction of inducible cyclic AMP early repressor (ICER) and other related CREM (cyclic AMP response element (CRE) modulator) mRNA within two hours of stimulation, and serves to repress beta1-AR gene transcription. And thirdly, we have identified another transcriptional repressor region in the beta1-AR gene, encompassing positions -396 to -367, and have identified the repressor molecule as a novel bZlP-like transcription factor. We will chronically-infuse various antidepressants into rats and rhesus macaques, and recover cortical specimens to identify the specific molecular mechanisms underlying beta1-AR mRNA down-regulation. This information may provide insiahts in the molecular role of the adrenerqic receptors in depression, and develop a better understandinq of the efficacy of antidepressant treatment. Thus, this R21 grant submission is responsive to objective 4 of PA-00-073, """"""""initial research and development for building significant future research"""""""". The primary experimental objectives of Specific Aim 1 are to verify that the RNA binding proteins HuR, hnRNP A1, and/or AUF-1 are the degradative molecules involved in antidepressant-induced beta1-AR mRNA down-regulation, and to determine whether antidepressants trigger the nucleocytoplasmic export of beta1-AR mRNAs, via interaction with HuR and other selective HuR ligands. The primary experimental objectives of Specific Aim 2 are to validate ICER and the novel bZlP-like transcription factor as potential repressors of beta1-AR gene expression during antidepressant therapy.
| Bai, Ying; Lu, Huafei; Machida, Curtis A (2006) CRM 1-mediated degradation and agonist-induced down-regulation of beta-adrenergic receptor mRNAs. Biochim Biophys Acta 1763:1076-89 |
| Li, Biao; Li, Xiaorong; Bai, Ying et al. (2004) Simian retrovirus serogroup 2 constitutive transport element recognizes the ribosomal L10-like protein and translocon gamma subunit-like protein in a yeast three-hybrid assay. Virus Res 99:69-80 |
| Bai, Ying; Kirigiti, Philbert; Li, Xiaorong et al. (2003) UV cross-linking/immunoprecipitation assay: glucocorticoid receptor-adrenergic receptor gene sequence interaction. Biotechniques 35:100-4, 106, 108-11 |
