Dual signalling by the adenosine A2a receptor involves activation of both N- and P-type calcium channels by different G proteins and protein kinases in the same striatal nerve terminals.

Many Gs-linked receptors have been reported to use multiple signalling pathways in transfected cels but few in their normal cell environment. We show that the adenosine A2a receptor uses two signalling pathways to increase the release of acetylcholine from striatal nerve terminals. One pathway involves activation of Gs, adenylyl acylase, protein kinase A, and P-type calcium channels; the other is mediated by a cholera toxin-insensitive G protein, protein kinase C, and N-type calcium channels. The effects of these two pathways are not additive, the second pathway being inhibited by the first; but they are equally sensitive to the A2a receptor antagonist KF17837. This demonstrates that the A2a receptor activates two signalling systems in striatal cholinergic neurons.