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Vol. 59, Issue 5, 1314-1323, May 2001
Departament de Bioquímica i Biologia Molecular, Facultat de
Química. Universitat de Barcelona, Spain
Chronic exposure of A1 adenosine receptors
(A1R) to A1R agonists leads to activation,
phosphorylation, desensitization, and internalization to intracellular
compartments of the receptor. Desensitization and internalization of
A1R is modulated by adenosine deaminase (ADA), an enzyme
that regulates the extracellular concentration of adenosine. ADA
interacts with A1R on the cell surface of the smooth muscle
cell line DDT1 MF-2, and both proteins are internalized following
agonist stimulation of the receptor. The mechanism involved in
A1R and ADA internalization upon agonist exposure is poorly understood in epithelial cells. In this report, we show that
A1R and ADA interact in LLC-PK1 epithelial
cells. Exposure of LLC-PK1 cells to A1R
agonists induces aggregation of A1R and ADA on the cell
surface and their translocation to intracellular compartments. Biochemical and cell biology assays were used to characterize the
intracellular vesicles containing both proteins after agonist treatment. A1R and ADA colocalized together with the
rafts marker protein caveolin. Filipin, a sterol-binding agent
that disrupts rafts (small microdomains of the plasma membrane), was
able to inhibit A1R internalization. In contrast, acid
treatment of the cells, which disrupts internalization via
clathrin-coated vesicles, did not inhibit agonist-stimulated
A1R internalization. We demonstrated that A1R
agonist N6-(R)-phenylisopropyl
adenosine promotes the translocation of A1R into
low-density gradient fractions containing caveolin. Furthermore, a direct interaction of the C-terminal domain of A1R with
caveolin-1 was demonstrated by pull down experiments. These results
indicate that A1R and ADA form a stable complex in the cell
surface of LLC-PK1 cells and that agonist-induced
internalization of the A1 adenosine receptor and ADA is
mediated by clathrin-independent endocytosis.
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