Indirect phosphorylation-dependent modulation of postsynaptic nicotinic acetylcholine responses by 5-hydroxytryptamine

Ionotropic nicotinic acetylcholine (ACh) receptors have been shown to be modulated by protein kinase‐mediated phosphorylation in vitro. Here we demonstrate that 5‐hydroxytryptamine (5‐HT) can downregulate postsynaptic nicotinic ACh responses, elicited in an identified arthropod motoneuron in situ, by a mechanism dependent on protein kinase activity. Serotonergic modulation can be mimicked by perfusion with membrane‐permeable analogues of either adenine (cAMP) or guanine (cGMP) cyclic nucleotides, and is prolonged in the presence of phosphodiesterase inhibitors. Furthermore, suppression of the ACh response by 5‐HT is blocked by specific competitive inhibitors of protein kinase A and G, as well as the broad specificity protein kinase inhibitor staurosporine. The protein phosphatase inhibitor cantharidin similarly blocks recovery of the ACh response from suppression mediated by 5‐HT. Thus, it appears that the nicotinic ACh response is modulated by a cAMP‐mediated phosphorylation‐dependent intracellular signalling pathway that is distinct from the direct block of mammalian nicotinic ACh receptors by 5‐HT previously reported in vitro.