Additivity and non-additivity between dopamine-, norepinephrine-, carbachol- and GABA-stimulated GTPase activity

The mode of coupling between neurotransmitter receptors and G proteins was investigated by agonist-induced high-affinity GTPase activity in rat striatal membranes. There was a simple additive relationship among dopamine-, carbachol-, and gamma-aminobutyric acid (GABA)-sensitive high-affinity GTPase activity in any combination, indicating that the respective receptors stimulated by these agonists (i.e., dopamine D2, pirenzepine-insensitive muscarinic, and GABAB receptors) interact independently with distinct pools of G proteins. Unexpectedly non-additivity was observed between dopamine- and norepinephrine-stimulation. This lack of additivity was apparently due to stimulation of the same dopamine D2 receptors by both dopamine and norepinephrine, since norepinephrine-stimulated high-affinity GTPase activity could be inhibited by dopaminergic but not adrenergic antagonists. The same non-additivity as seen in rat striatum was confirmed in the membranes prepared from cultured mouse fibroblast cells co-transfected with dopamine D2 and adenosine A2A receptors. The implication of the (non-)additivity between receptor-mediated high-affinity GTPase activity was discussed with a consideration of the possible underlying molecular mechanism.