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Jajoo S, Mukherjea D, Kumar S, Sheth S, Kaur T, Rybak LP, Ramkumar V: Role of beta-arrestin1/ERK MAP kinase pathway in regulating adenosine A1 receptor desensitization and recovery. Am J Physiol Cell Physiol. 2010 Jan;298(1):C56-65. Epub 2009 Oct 14.
Exposure of cells to adenosine receptor (AR) agonists leads to receptor uncoupling from G proteins and downregulation of the A (1) AR. The receptor levels on the cell surface generally recover on withdrawal of the agonist, because of either translocation of the sequestered A (1) AR back to plasma membrane or de novo synthesis of A (1) AR. To examine the mechanism (s) underlying A (1) AR downregulation and recovery, we treated ductus deferens tumor (DDT (1) MF-2) cells with the agonist R-phenylisopropyladenosine (R-PIA) and showed a decrease in membrane A (1) AR levels by 24 h, which was associated with an unexpected 11-fold increase in A (1) AR mRNA. Acute exposure of these cells to R-PIA resulted in a rapid translocation of beta-arrestin1 to the plasma membrane. Knockdown of beta-arrestin1 by short interfering RNA (siRNA) blocked R-PIA-mediated downregulation of the A (1) AR, suppressed R-PIA-dependent ERK1/2 and activator protein-1 (AP-1) activity, and reduced the induction of A (1) AR mRNA. Withdrawal of the agonist after a 24-h exposure resulted in rapid recovery of plasma membrane A (1) AR. This was dependent on the de novo protein synthesis and on the activity of ERK1/2 but independent of beta-arrestin1 and nuclear factor-kappaB. Together, these data suggest that exposure to A (1) AR agonist stimulates ERK1/2 activity via beta-arrestin1, which subserves receptor uncoupling and downregulation, in addition to the induction of A (1) AR expression. We propose that such a pathway ensures both the termination of the agonist signal and recovery by priming the cell for rapid de novo synthesis of A (1) AR once the drug is terminated. |
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