G_i protein coupling to adenosine A₁-A_2A receptor heteromers in human brain caudate nucleus

Authors: Casadó, Vicent; Barrondo, Sergio; Spasic, Milena; Callado, Luis F.; Mallol, Josefa; Canela, Enric; Lluís, Carmen; Meana, Javier; Cortés, Antoni; Sallés, Joan; Franco, Rafael

Source: Journal of Neurochemistry, Volume 114, Number 4, August 2010 , pp. 972-980(9)

Publisher: Wiley-Blackwell

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Abstract:

J. Neurochem. (2010) 114, 972-980. Abstract

Pharmacological characterization of adenosine A₁ and A_2A receptors in human brain caudate nucleus membranes led to non-cooperative binding of radiolabelled ligands. In human caudate nucleus but not in cortex, the agonist binding to A₁ receptors was modulated by the agonist binding to A_2A receptors indicating a functional negative cross-talk. Accordingly, the A₁ receptor-activation-mediated G_i-dependent guanosine 5′-o-(3-[³⁵S]thio-triphosphate) binding was modulated by agonist binding to A_2A receptors. A_2A receptors occupation led to a decrease in the potency of A₁ receptor agonists. These results indicate that A₁ but not A_2A receptors activation, likely occurring at low adenosine concentrations, engages a G_i-mediated signaling; however, when both receptors are occupied by adenosine, there is an A_2A receptor-mediated impairment of G_i-operated transducing units. These findings are relevant to get insight into the complex relationships derived from co-expression of multiple neurotransmitter/neuromodulator receptors subtypes that individually are coupled to different G proteins. A further finding was the demonstration that the A_2A receptor agonist, CGS 21680, at high concentrations able to significantly bind to the A₁ receptor, behaved as a partial agonist of the later receptor. This fact might be taken into account when characterizing CGS 21680 actions in human cells expressing A₁ receptors when the compound is used at micromolar concentrations.

Keywords: adenosine receptors; cell signaling; human brain; ligand binding; receptor heteromers

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1471-4159.2010.06810.x

Affiliations: 1: Biochemistry and Molecular Biology Department, University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Barcelona, Spain

Publication date: 2010-08-01