Cyclopentyladenosine‐Induced Homologous Down‐Regulation of A1 Adenosine Receptors (A1AR) in Intact Neurons Is Accompanied by Receptor Sequestration but Not a Reduction in A1AR mRNA Expression or G Protein α‐Subunit Content

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Abstract
We showed previously that exposure of cerebellar granule cells to the A1 adenosine receptor (A1AR)-selective agonist, cyclopentyladenosine, decreases A1AR density and G protein coupling corresponding to blunted agonist-induced adenylyl cyclase (EC 4.6.1.1) inhibition. We have now determined that A1AR-mediated adenylyl cyclase inhibition was desensitized in a homologous manner. Carbachol- and baclofen-induced inhibition of adenylyl cyclase was unaffected by 48-h exposure to 10 microM cyclopentyladenosine. Expression of G protein alpha-subunits was not affected dramatically by agonist exposure. The fraction of sequestered A1AR was increased significantly at 4, 24, and 48 h of cyclopentyladenosine exposure (35, 57, and 81% increase over control, respectively). The time course of agonist-induced A1AR sequestration was slower than that reported for other G protein-coupled receptors. Incubation with the adenosine receptor antagonist, 8-p-sulfophenyltheophylline or adenosine deaminase did not alter sequestration significantly. Neither steady-state A1AR mRNA levels nor transcript stability was affected by 48-h agonist exposure. We determined that A1AR half-life in cerebellar granule cells is 20.9 h, which is considerably longer than that reported for several other G protein-coupled receptors. The slow time course of A1AR sequestration and the stability of the corresponding mRNA may be a reflection of the tonic inhibitory tone exerted by adenosine in brain.

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