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Research Article

Role of β-Arrestin1/ERK MAP Kinase Pathway in Regulating Adenosine A₁ Receptor Desensitization and Recovery

¹Southern Illinois University School of Medicine

Submitted 30 April 2009 ; revised 28 September 2009 ; accepted in final form 29 September 2009

Exposure of cells to the adenosine receptor (AR) agonists leads to receptor uncoupling from G proteins and down-regulation of the A₁AR. The receptor levels on the cell surface generally recover upon withdrawal of the agonist, due to either translocation of the sequestered A₁AR back to plasma membrane or to de novo synthesis of A₁AR. To examine the mechanism(s) underlying A₁AR down-regulation and recovery, we treated ductus deferens tumor (DDT₁ MF-2) cells with the agonist, R-phenylisopropyladenosine (R-PIA), and showed a decrease in membrane A₁AR levels by 24 h, which was associated with an unexpected 11-fold increase in A₁AR mRNA. Acute exposure of these cells to R-PIA resulted in a rapid translocation of β-arrestin1 to the plasma membrane. Knockdown of β-arrestin1 by short interfering (si) RNA blocked R-PIA-mediated down-regulation of the A₁AR, suppressed R-PIA-dependent ERK1/2 and activator protein-1 (AP-1) activity, and reduced the induction of A₁AR mRNA. Withdrawal of the agonist following a 24 h exposure resulted in rapid recovery of plasma membrane A₁AR. This was dependent on the de novo protein synthesis and on the activity of ERK1/2, but independent of β-arrestin1 and nuclear factor (NF)-B. Taken together, these data suggest that exposure to A₁AR agonist stimulates ERK1/2 activity via β-arrestin1 which subserves receptor uncoupling and down-regulation, in addition to the induction of A₁AR 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 A₁AR once the drug is terminated.

Adenosine A1 Receptor; Desensitization; β-arrestin1; ERK MAP Kinase