Adenosine Regulates via Two Different Types of Receptors, the Accumulation of Cyclic Amp in Cultured Brain Cells

Abstract

In cell cultures of glial character derived from perinatal mouse brain adenosine elicits two effects. (a) At submicromolar concentrations I t inhibits the increase in the intracellular level of cyclic AMP caused by j-adrenoceptor agonists. (b) At concentrations above micromolar it increases the level of cyclic AMP in the cultures. These two effects are mediated by two different adenosine receptors present on the outer surface of the cells. This is concluded from the following evidence. (a) Both effects are antagonized by methylxanthines but not by blockage of adenosine uptake or inhibition of phosphodiesterase activity. (b) In both cases activity depends on the integrity of the ribose moiety of the nucleotide. Substituents of the purine system are tolerated comparatively well. (c) The order of potency of adenosine analogues is different for the two effects. We suggest the name A1 receptors for those that mediate the inhibition and A2 for those that mediate the stimulation of cyclic AMP accumulation.

Carbamazepine distinguishes between adenosine receptors that mediate different second messenger responses

“…Theincubations were terminated by removal of the buffer and the addition of 1 ml ice-coJd trichloroacetic acid (10% w jv). After removal of the trichloroacetic acid by extraction with diethyl ether (3 times 4 ml), the samples were fractionated by anion chromatography on small Dowex columns (Bio Rad AG 1 X 2) as described (Van Calker et al, 1979). The cyclic AMP content in the samples was determined by a commercially available protein binding assay (Amersham).…”

“…Astrohlast cultures were prepared by mechanical dissociation of newborn mouse or rat brain and cultivated as described previously (Van Calker et al, 1979).…”

Carbamazepine-Induced Upregulation of Adenosine A1-Receptors in Astrocyte Cultures Affects Coupling to the Phosphoinositol Signaling Pathway

“…Adenosine A 1 -and A 2 -receptor subtypes were originally distinguished by their differential effects on adenylyl cyclase (van Calker et al 1978(van Calker et al , 1979, but more recent findings have revealed coupling of adenosine receptors to other signal transduction systems including phospholipase C (PLC) (Miller and Hoffman 1994;Fredholm et al 1994). Very often, the coupling of adenosine A 1 -receptors to PLC ␤ is synergistic with the stim- NO .…”

“…CBZ may even have advantages as compared to lithium in the treatment and prophylaxis of schizoaffective and rapid cycling bipolar disorders (for review see Solomon et al 1995). Among the various pharmacological effects of CBZ, its activity as a specific antagonist at adenosine A 1 receptors (van Calker et al 1991;Biber et al, 1996) may be particularly important, because this property could lead to alterations in the responsiveness of signal transduction systems in the brain (van Calker et al 1998), a mechanism believed to be instrumental also to lithium's beneficial effects in affective disorders (for review see Manji et al 1995).Adenosine A 1 -and A 2 -receptor subtypes were originally distinguished by their differential effects on adenylyl cyclase (van Calker et al 1978(van Calker et al , 1979, but more recent findings have revealed coupling of adenosine receptors to other signal transduction systems including phospholipase C (PLC) (Miller and Hoffman 1994;Fredholm et al 1994). Very often, the coupling of adenosine A 1 -receptors to PLC ␤ is synergistic with the stim- NO .…”

“…Adenosine A 1 -and A 2 -receptor subtypes were originally distinguished by their differential effects on adenylyl cyclase (van Calker et al 1978(van Calker et al , 1979, but more recent findings have revealed coupling of adenosine receptors to other signal transduction systems including phospholipase C (PLC) (Miller and Hoffman 1994;Fredholm et al 1994). Very often, the coupling of adenosine A 1 -receptors to PLC ␤ is synergistic with the stim-ulation evoked by other receptors, such as ␣ 1 -adrenergic receptors (El-Etr et al 1989;Biber et al 1996Biber et al , 1997, histamine H 1 -receptors (Dickenson and Hill 1994), muscarinic receptors (Biden and Browne 1993), or thyrotropin receptors (Okajima et al 1995).…”