Signaling Pathway from the Human Adenosine A3 Receptor Expressed in Chinese Hamster Ovary Cells to the Extracellular Signal-Regulated Kinase 1/2

doi:10.1124/mol.62.5.1137

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Vol. 62, Issue 5, 1137-1146, November 2002

Signaling Pathway from the Human Adenosine A₃ Receptor Expressed in Chinese Hamster Ovary Cells to the Extracellular Signal-Regulated Kinase 1/2

Gunnar Schulte and Bertil B. Fredholm

Section of Molecular Neuropharmacology, Department of Physiology & Pharmacology, Karolinska Institutet, Stockholm, Sweden

Adenosine activates four different receptors, the A₁, A_2A, A_2B, and the A₃ receptors, all of which are G protein-coupled.We have previously shown that stimulation of the human adenosineA₃ receptor can induce phosphorylation of extracellular signal-regulatedkinase (ERK1/2). Here we show that the adenosine receptor agonist5' N-ethylcarboxamidoadenosine (NECA) induces phosphorylationand activation of ERK1/2 in Chinese hamster ovary (CHO) cellsexpressing the human adenosine A₃ receptor (CHO A₃ cells) withthe same potency. Pretreatment with pertussis toxin abolishedthe effect, which also could be blunted by overexpressing the $beta$ $gamma$ -sequestering peptide $beta$ -adrenergic receptor kinase-ct, implicatingthe involvement of $beta$ $gamma$ subunits released from G_i/o proteins. Activationof phosphatidylinositol-3-kinase (PI3K) by adenosine A₃ receptorsis inferred from a dose-dependent Ser-phosphorylation of the proteinkinase B (Akt). Furthermore the ERK1/2 phosphorylation was sensitiveto the PI3K inhibitors wortmannin and LY294002 (2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-onehydrochloride) and the MEK inhibitor PD98059 (2'-amino-3'-methoxyflavone),whereas chelation of Ca²⁺ with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acidtetrakis (acetoxymethyl ester) and long-term treatment with phorboldibutyratedid not decrease the adenosine A₃ receptor-mediated ERK1/2 phosphorylation.Thus, Ca²⁺ mobilization and conventional and novel protein kinase C (PKC)isoforms are not involved in this pathway. The atypical PKC $zeta$ wasnot activated by NECA and thus not involved in the A₃ receptor-mediatedERK1/2 phosphorylation. NECA stimulation of CHO A₃ cells activatedthe small G protein Ras and the dominant negative mutant RasS17Nprevented the phosphorylation of ERK1/2. In conclusion, the adenosineA₃ receptor recruits a pathway that involves $beta$ $gamma$ release from G_i/o,PI3K, Ras, and MEK to induce ERK1/2 phosphorylation and activation,whereas signaling is independent of Ca²⁺, PKC, and c-Src.

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