Schloss P, Betz H
Abteilung Neurochemie, Max-Planck-Institut für Hirnforschung, Frankfurt, Germany.
Biochemistry. 1995 Oct 3;34(39):12590-5. doi: 10.1021/bi00039a014.
Antidepressant drugs block the uptake of serotonin into serotonergic nerve terminals and blood platelets. Here, binding of the tricyclic antidepressant [3H]imipramine to the recombinant rat serotonin transporter SERT1 expressed in human embryonic kidney cells was found to be nonhomogeneous. Scatchard analysis and competition experiments revealed the existence of two distinct antidepressant binding sites. At site 1, [3H]imipramine binding was strictly sodium-dependent with an apparent KD of approximately 10 nM. In contrast, [3H]imipramine binding to site 2 occurred also in the absence of sodium and exhibited a lower affinity. Binding of the nontricyclic antidepressant [3H]citalopram was observed 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 approximately 5-fold lower. These data provide a molecular explanation for the distinct pharmacological actions of different antidepressants.
抗抑郁药物可阻止血清素被摄取到血清素能神经末梢和血小板中。在此，发现三环抗抑郁药[3H]丙咪嗪与人胚肾细胞中表达的重组大鼠血清素转运体SERT1的结合是非均匀的。Scatchard分析和竞争实验揭示了存在两个不同的抗抑郁药结合位点。在位点1，[3H]丙咪嗪的结合严格依赖于钠，其表观解离常数约为10 nM。相比之下，[3H]丙咪嗪在位点2的结合在无钠的情况下也会发生，且亲和力较低。非三环抗抑郁药[3H]西酞普兰的结合仅在位点2观察到。该载体的天然底物血清素在两个位点竞争性抑制抗抑郁药的结合；然而，它在位点2的亲和力约低5倍。这些数据为不同抗抑郁药的独特药理作用提供了分子解释。
