Alpha-adrenoceptor stimulation, but not muscarinic stimulation, increases cyclic AMP accumulation in brain slices due to protein kinase C mediated enhancement of adenosine receptor effects.
In the present study, using rat hippocampal slices, we have further examined the stimulatory effect of alpha 1-adrenoceptors on the accumulation of cyclic AMP, which is known to depend on calcium and adenosine. The addition of noradrenaline (NA) stimulated the accumulation of [3H]inositol phosphates in [3H]inositol-treated slices. This effect was shared by carbachol (10-100 mumol l-1) but not by the adenosine receptor agonist 2-chloroadenosine (100 mumol l-1). The stimulatory effect of the alpha-agonists (phenylephrine or NA + propranolol) on cyclic AMP was shared by a diacylglycerol derivative, sn-1-oleyl-2-acetyl glycerol (OAG), and by the tumour-promoting phorbol esters phorboldibutyrate (PDiBu) and tetradecanoyl phorbol acetate (TPA). PDiBu caused a translocation of protein kinase C from soluble to particulate fractions. The effects of PDiBu and alpha-adrenoceptor stimulation on cyclic AMP were not additive. Surprisingly, carbachol (1-1000 mumol l-1) did not stimulate cyclic AMP accumulation in rat hippocampal slices either in the presence or in the absence of an adenosine receptor agonist. The results are compatible with the opinion that alpha-adrenoceptor stimulating drugs enhance the formation of inositol phosphates and diacylglycerol, which synergistically activate protein kinase C, which in turn augments the stimulation of cyclic AMP formation. Thus, a neurotransmitter whose principal biological effect is to stimulate inositol phosphate formation can influence cyclic AMP formation by virtue of an interaction with the actions of the ubiquitous neuromodulator adenosine. The fact that the effect of the alpha-receptor stimulation was not mimicked by a muscarinic agonist could indicate that other factors besides activation of inositol phospholipid hydrolys are important for this receptor-receptor interaction.
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004075:Diglycerides / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism*; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects*
D000316:Adrenergic alpha-Agonists; D004075:Diglycerides; D007295:Inositol Phosphates; D010703:Phorbol Esters; D011976:Receptors, Muscarinic; D002217:Carbachol; D000242:Cyclic AMP; D011493:Protein Kinase C; D009638:Norepinephrine