Role of β-arrestin1/ERK MAP kinase pathway in regulating adenosine A1 receptor desensitization and recovery

Sarvesh Jajoo, Debashree Mukherjea, Sunny Kumar, Sandeep Sheth, Tejbeer Kaur, Leonard P. Rybak, Vickram Ramkumar

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Exposure of cells to adenosine receptor (AR) agonists leads to receptor uncoupling from G proteins and downregulation of the A1AR. The receptor levels on the cell surface generally recover on withdrawal of the agonist, because of either translocation of the sequestered A1AR back to plasma membrane or de novo synthesis of A1AR. To examine the mechanism(s) underlying A1AR downregulation 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 RNA (siRNA) blocked R-PIA-mediated downregulation 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 after 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-κB. Together, these data suggest that exposure to A1AR agonist stimulates ERK1/2 activity via β-arrestin1, which subserves receptor uncoupling and downregulation, 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.

Original languageEnglish (US)
Pages (from-to)C56-C65
JournalAmerican Journal of Physiology - Cell Physiology
Volume298
Issue number1
DOIs
StatePublished - Jan 2010
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cell Biology

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