title: Allosteric interaction between the site labeled by [3H]imipramine and the serotonin transporter in human platelets.
abstract: The nature of interaction between the site labeled by [3H]imipramine (IMI) and the 5-hydroxytryptamine (5-HT, serotonin) transporter in human platelets was examined. The sulfhydryl characterizing agent N-ethylmaleimide (NEM) differentially affected [3H]5-HT uptake and [3H]IMI binding in human platelet preparations. Concentrations of NEM that completely abolished [3H]5-HT uptake only minimally reduced [3H]IMI binding. Examining the effect of IMI on the kinetics of human platelet [3H]5-HT uptake revealed significant reductions in maximal velocity (Vmax) without altering affinity (Km). IC50 values for selected uptake blockers on [3H]IMI binding and [3H]5-HT uptake were determined. IC50 values of these compounds for uptake and binding revealed that agents such as IMI, chlorpromazine, amitriptyline, and nisoxetine were preferential inhibitors of [3H]IMI binding whereas fluoxetine, CL 216, 303, pyrilamine, and bicifadine were preferential [3H]5-HT uptake blockers. 5-HT was a weak displacer of [3H]IMI binding (IC25 = 3.0 microM) and exhibited a rather low Hill coefficient (nH app = 0.46). Results reported herein support the notion of an allosteric interaction between the [3H]IMI binding site and the 5-HT transporter complex in human platelets.
mesh_terms: D000639:Amitriptyline / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002746:Chlorpromazine / Q000494:pharmacology; D005033:Ethylmaleimide / Q000494:pharmacology; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007099:Imipramine / Q000097:blood*; D007700:Kinetics; D011738:Pyrilamine / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000378:metabolism*
chemical_list: D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D011985:Receptors, Serotonin; D005473:Fluoxetine; C011386:nisoxetine; D000639:Amitriptyline; C034438:bicifadine; D011738:Pyrilamine; D005033:Ethylmaleimide; D007099:Imipramine; D002746:Chlorpromazine