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Eur J Pharmacol. 2011 Nov 30;670(2-3):365-71. doi: 10.1016/j.ejphar.2011.09.027. Epub 2011 Sep 21.

Desensitization of adenosine A(1) receptors in rat immature cortical neurons.

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Departamento de Química Inorgánica, Orgánica y Bioquímica, Facultad de Ciencias Químicas, Centro Regional de Investigaciones Biomédicas, Universidad de Castilla-La Mancha, Ciudad Real, Spain


Adenosine plays an important neuroprotective role in brain, usually mediated by the activation of adenosine A₁ receptors. Prolonged activation of a G-protein-coupled receptor generally leads to the partial loss of the responsiveness of receptor-mediated transduction pathways (desensitization). Rat immature cortical neurons were treated with 100 nM⁻N⁶-phenylisopropyladenosine (R-PIA), a selective A₁ receptor agonist, and the effect on adenosine A₁ receptor/adenylyl cyclase pathway was studied. Incubation with R-PIA for 6, 12, 24 and 48 h elicited a time-dependent decrease in adenosine A₁ receptors in plasma membranes (92, 58, 43 and 26% of control, respectively), which was associated with variations in microsomal fraction (21, 56, 124 and 233% of control, respectively), suggesting the internalization and down-regulation of adenosine A₁ receptors. Moreover, real-time PCR assays showed a significant increase in mRNA levels coding adenosine A₁ receptor after the longest treatment period (48 h). In addition, αGi₁₋₂ protein levels detected in microsomes and mRNA levels coding αGi₁ protein were increased after 48 h of treatment with R-PIA, suggesting the synthesis of new αGi₁ proteins. Finally, adenylyl cyclase inhibition elicited by 2-Chloro-N6-cyclopentyladenosine (CPA), a selective adenosine A₁ receptor agonist, was significantly reduced after 12, 24 and 48h of treatment (37, 24 and 23%, respectively) as compared to controls (54%), suggesting the desensitization of adenosine A₁ receptor/adenylyl cyclase pathway. These results suggest that adenosine A₁ receptors desensitize slowly after prolonged receptor activation in immature cortical neurons, showing mechanisms of desensitization similar to those described not only in fetal but also in adult rat brain.

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