HETEROGENEITY OF ANTIDEPRESSANT BINDING-SITES ON THE RECOMBINANT RAT SEROTONIN TRANSPORTER SERT1

Antidepressant drugs block the uptake of serotonin into serotonergic n erve terminals and blood platelets. Here, binding of the tricyclic ant idepressant [H-3]imipramine to the recombinant rat serotonin transport er SERT1 expressed in human embryonic kidney cells was found to be non homogeneous. Scatchard analysis and competition experiments revealed t he existence of two distinct antidepressant binding sites. At site 1, [H-3]imipramine binding was strictly sodium-dependent with an apparent K-D of similar to 10 nM. In contrast, [H-3]imipramine binding to site 2 occurred also in the absence of sodium and exhibited a lower affini ty. Binding of the nontricyclic antidepressant [3H]citalopram was obse rved only at site 2. The natural substrate of this carrier, serotonin, competitively inhibited antidepressant binding at both sites; however , its affinity to site 2 was similar to 5-fold lower. These data provi de a molecular explanation for the distinct pharmacological actions of different antidepressants.