Prolonged in vitro exposure of rat brain slices to adenosine analogues: Selective desensitization of adenosine A1 but not A2 receptors
- 2 November 1992
- journal article
- Published by Elsevier BV in European Journal of Pharmacology: Molecular Pharmacology
- Vol. 227 (3), 317-324
- https://doi.org/10.1016/0922-4106(92)90010-s
Abstract
Agonist-induced desensitization of adenosine A1 and A2 receptors was studied in rat striatum slices maintained in carbo-oxygenated Krebs buffer. Slices were exposed to adenosine analogues (either cyclo-penlyl-adenosine or N-ethyl-carboxamido-adenosine) for selected time periods (15–60 min) and repeatedly washed at the end of agonist exposure. Agonist-induced changes of adenosine receptors were then evaluated in P2 fractions prepared from slices by measuring A1 and A2 rcccptor-regulated adenylatc cyclase. A1 receptors were rapidly desensitized by agonist exposure, as shown by a gradual loss of A1 receptor-mediated inhibition of basal cyclase activity and cAMP formation, which was evident within 15–30 min after addition of the adenosine analogue. Agonist-induced desensitization of A1 receptors was dose- and time-dependent, and seemed quicker in onset with cyclo-pentyl-adenosine, according to the higher A1 selectivity of this receptor agonist, with respect to N-ethyl-carboxamido-adenosine. Binding of the A1-sclective agonist [3H]cyclo-hexyl-adenosine was unaffected by the desensitization procedure at any of the exposure periods utilized, suggesting that an uncoupling of A1 receptors from their transduction system is indeed responsible for the loss of functional activity. Loss of A1 receptor function was accompanied by a time-dependent amplification of A2 receptor-mediated stimulation of adenylete cyciase activity, likely due to an ‘unmasking’ of A2 stimulatory receptor function as a consequence of the desensitizalion of A1 inhibitory receptors. All these effects could be completely counteracted by the concomitant exposure to an adenosine receptor antagonist, and specifically involved the coupling mechanisms of adenosine receptors with their effector system. It is therefore concluded that the prolonged exposure of brain slices to adenosine analogues rapidly and selectively desensitizes A14 receptors in the absence of any loss of A2 receptor function. These receptor adaptive changes might be relevant to brain pathological conditions characterized by over-exposure to endogenous adenosine.Keywords
This publication has 22 references indexed in Scilit:
- Expression and desensitisation of A2 purinoceptors on cultured bovine aortic endothelial cellsCardiovascular Research, 1989
- Cyclohexyl adenosine protects against neuronal death following ischemia in the CA1 region of gerbil hippocampus.Stroke, 1988
- Neuroprotective effects of adenosineTrends in Pharmacological Sciences, 1988
- Increases in Cerebral Cortical Perfusate Adenosine and Inosine Concentrations during Hypoxia and IschemiaJournal of Cerebral Blood Flow & Metabolism, 1987
- Purine Receptors in Mammalian Tissues: Pharmacology and Functional SignificanceAnnual Review of Pharmacology and Toxicology, 1987
- Prolonged postictal depression in amygdala-kindled rats by the adenosine analog, l-phenylisopropyladenosineExperimental Neurology, 1985
- Is Adenosine an Endogenous Anticonvulsant?Epilepsia, 1985
- Differential location of adenosine A1 and A2 receptors in striatumNeuroscience Letters, 1983
- Differential Binding Properties of Adenosine Receptor Agonists and Antagonists in BrainJournal of Neurochemistry, 1983
- A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye bindingAnalytical Biochemistry, 1976