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 [125I]alpha-bungarotoxin binding to Torpedo acetylcholine receptor membranes (IC(50)=8.5+/-0.32 mM) and [3H]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, [3H]5-HT photoincorporates into alphaTyr(190), alphaCys(192) and alphaCys(193). Functional studies using the human clonal cell line TE671/RD, show that 5-HT is a weak inhibitor (IC(50)=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 [3H]thienylcyclohexylpiperidine binding to the desensitized Torpedo acetylcholine receptor channel (IC(50)=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.
Blanton
M P
MP
Department of Pharmacology, Texas Tech University, Health Sciences Center, 3601 4th Street, Lubbock, TX, USA. phrmpb@ttuhsc.edu
McCardy
E A
EA
Fryer
J D
JD
Liu
M
M
Lukas
R J
RJ
D000818:Animals; D001665:Binding Sites; D002038:Bungarotoxins / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000378:metabolism; D019920:Photoaffinity Labels; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology*; D014101:Torpedo
D002038:Bungarotoxins; D019920:Photoaffinity Labels; D011978:Receptors, Nicotinic; D012701:Serotonin; C012058:tenocyclidine; D010622:Phencyclidine