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.
Butt
S J B
SJ
New York University Medical Center, Developmental Genetics Program, Skirball Institute, 4th Fl 540 First Ave, New York, NY 10016, USA.
Pitman
R M
RM
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002490:Central Nervous System / Q000166:cytology* / Q000187:drug effects; D003058:Cockroaches; D000242:Cyclic AMP / Q000494:pharmacology; D006152:Cyclic GMP / Q000494:pharmacology; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000528:radiation effects; D009046:Motor Neurons / Q000187:drug effects / Q000528:radiation effects; D018408:Patch-Clamp Techniques / Q000379:methods; D010766:Phosphorylation / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology*; D019311:Staurosporine / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000528:radiation effects; D013806:Theophylline / Q000494:pharmacology; D013997:Time Factors
D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D011978:Receptors, Nicotinic; D012701:Serotonin; D013806:Theophylline; D000242:Cyclic AMP; D006152:Cyclic GMP; D019311:Staurosporine; D000109:Acetylcholine