Potentiated cAMP Rise in Metabotropically Stimulated Rat Cultured Astrocytes by a Ca²⁺‐related A_l/k₂ Adenosine Receptor Cooperation

<jats:title>Abstract</jats:title><jats:p>Adenosine agonists favoured an intracellular Ca<jats:sup>2+</jats:sup> rise in cultured type 1 astrocytes if the metabotropic glutamate receptors were concomitantly stimulated by (2<jats:italic>S</jats:italic>,1′<jats:italic>s</jats:italic>, 2′<jats:italic>s</jats:italic>)‐2‐(carboxycyclopropyl) glycine (<jats:sc>l</jats:sc>‐CCG‐I; group II agonist), quisqualate (group I agonist) or 1 ‐aminocyclopentane‐<jats:italic>trans</jats:italic>‐1,3‐dicarboxylic acid (<jats:italic>t</jats:italic>‐ACPD; group VII agonist). Since the generation of a Ca<jats:sup>2+</jats:sup> signal reflected a newly adopted adenosine A<jats:sub>1</jats:sub> receptor action, we tested the possible consequence that the established opposing control of the cellular cAMP content by inhibitory A<jats:sub>1</jats:sub> and stimulatory A<jats:sub>2</jats:sub> receptor activation was also altered. During metabotropic receptor stimulation by L‐CCG‐I, quisqualate or <jats:italic>t</jats:italic>‐ACPD, the non‐selective adenosine agonist 2‐chloroadenosine (CI‐adenosine) caused a potentiated cAMP increase which markedly exceeded that produced by CI‐adenosine alone. This cAMP potentiation resulted from altered and Ca<jats:sup>2+</jats:sup>‐dependent A<jats:sub>1</jats:sub>/A<jats:sub>2</jats:sub> receptor cooperation. It was abolished by A<jats:sub>1</jats:sub> receptor blockade and could not be achieved in the presence of <jats:italic>t</jats:italic>‐ACPD by the A<jats:sub>1</jats:sub> agonist R(‐)<jats:italic>N</jats:italic><jats:sup>6</jats:sup>‐(2‐phenylisopropyl)‐adenosine or by the A<jats:sub>2</jats:sub> agonist 5′‐<jats:italic>N</jats:italic>‐ethyl carboxyamidoadenosine alone, but was obtained using their combination. The cAMP potentiation was blocked by intracellular Ca<jats:sup>2+</jats:sup> chelation and the required A<jats:sub>1</jats:sub> receptor action could be mimicked by a Ca<jats:sup>2+</jats:sup> signal generated by the P<jats:sub>2y</jats:sub> receptor agonist adenosine 5β‐(β‐thio) diphosphate. The results support the conclusion that nanomolar concentrations of adenosine may influence astrocyte reactions by stimulating the Ca<jats:sup>2+</jats:sup> and cAMP‐dependent signalling cascade.</jats:p>