Role of beta-arrestin1/ERK MAP kinase pathway in regulating adenosine A1 receptor desensitization and recovery.
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.
Jajoo
Sarvesh
S
PO Box 19629, SIU School of Medicine, Springfield, IL 62794, USA. vramkumar@siumed.edu
Mukherjea
Debashree
D
Kumar
Sunny
S
Sheth
Sandeep
S
Kaur
Tejbeer
T
Rybak
Leonard P
LP
Ramkumar
Vickram
V
D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002455:Cell Division; D006224:Cricetinae; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D008647:Mesocricetus; D009130:Muscle, Smooth / Q000166:cytology / Q000502:physiology; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D043682:Receptor, Adenosine A1 / Q000187:drug effects / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014649:Vas Deferens / Q000166:cytology / Q000502:physiology; D000071557:beta-Arrestins
D019390:Arrestins; D034741:RNA, Small Interfering; D043682:Receptor, Adenosine A1; D000071557:beta-Arrestins; D010660:Phenylisopropyladenosine; D048049:Extracellular Signal-Regulated MAP Kinases