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J Biol Chem, Vol. 273, Issue 28, 17610-17617, July 10, 1998

Adenosine Deaminase and A₁ Adenosine Receptors Internalize Together following Agonist-induced Receptor Desensitization

From the Departament de Bioquímica i Biologia Molecular, Facultat de Química, Universitat de Barcelona, 08028 Barcelona, Catalunya, Spain

A₁ adenosine receptors (A₁Rs) and adenosine deaminase (ADA; EC 3.5.4.4) interact on the cell surface of DDT₁MF-2 smooth muscle cells. The interaction facilitates ligand binding and signaling via A₁R, but it is not known whether it has a role in homologous desensitization of A₁Rs. Here we show that chronic exposure of DDT₁MF-2 cells to the A₁R agonist, N⁶-(R)-(phenylisopropyl)adenosine (R-PIA), caused a rapid aggregation or clustering of A₁ receptor molecules on the cell membrane, which was enhanced by pretreatment with ADA. Colocalization between A₁R and ADA occurred in the R-PIA-induced clusters. Interestingly, colocalization between A₁R and ADA also occurred in intracellular vesicles after internalization of both protein molecules in response to R-PIA. Agonist-induced aggregation of A₁Rs was mediated by phosphorylation of A₁Rs, which was enhanced and accelerated in the presence of ADA. Ligand-induced second-messenger desensitization of A₁Rs was also accelerated in the presence of exogenous ADA, and it correlated well with receptor phosphorylation. However, although phosphorylation of A₁R returned to its basal state within minutes, desensitization continued for hours. The loss of cell-surface binding sites (sequestration) induced by the agonist was time-dependent (t1/2= 10 ± 1 h) and was accelerated by ADA. All of these results strongly suggest that ADA plays a key role in the regulation of A₁Rs by accelerating ligand-induced desensitization and internalization and provide evidence that the two cell surface proteins internalize via the same endocytic pathway.

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