5-Hydroxytryptamine interaction with the nicotinic acetylcholine receptor

The present study examines the interaction of the neurotransmitter 5-hydroxytryptamine (5-HT) with muscle-type nicotinic acetylcholine receptors. 5-HT inhibits the initial rate of [I-125]alpha-bungarotoxin binding to Torpedo acetylcholine receptor membranes (IC50 = 8.5 +/- 0.32 mM) and [H-3]5-HT can be photoincorporated into acetylcholine receptor subunits, with labeling of the alpha-subunit inhibitable by both agonists and competitive antagonists. Within the agonist-binding domain, [H-3]5-HT photoincorporates into alpha Tyr(190), alpha Cys(192) and alpha Cys(193). Functional studies using the human clonal cell line TE671/RD, show that 5-HT is a weak inhibitor (IC50 = 1.55 +/- 0.25 mM) of acetylcholine receptor activity. In this regard, agonist-response profiles in the absence and presence of 5-HT indicate a noncompetitive mode of inhibition. In addition, 5-HT displaces high affinity [H-3]thienylcyclohexylpiperidine binding to the desensitized Torpedo acetylcholine receptor channel (IC50 = 1.61 +/- 0.07 mM). Collectively, these results indicate that 5-HT interacts weakly with the agonist recognition site and inhibits receptor function noncompetitively by binding to the acetylcholine receptor channel. (C) 2000 Elsevier Science B.V. All rights reserved.