Inhibitory and regulatory binding sites on the rat brain serotonin transporter: molecular weight of the [3H]paroxetine and [3H]citalopram binding proteins

• Published in: European journal of pharmacology Vol. 189; no. 2-3; p. 129
• Main Authors: Plenge, P, Mellerup, E T, Nielsen, M
• Format: Journal Article
• Language: English
• Published: Netherlands 18.09.1990
• Subjects: Animals; Biological Transport, Active; Brain - metabolism; Carrier Proteins - metabolism; Citalopram - metabolism; Half-Life; In Vitro Techniques; Kinetics; Models, Biological; Molecular Weight; Paroxetine; Piperidines - metabolism; Rats; Receptors, Serotonin - metabolism
• ISSN: 0014-2999
• DOI: 10.1016/0922-4106(90)90016-Q

Citalopram binds with high affinity to a specific binding site located on the serotonin (5-HT) transporter in 5-HT neurons. The binding affinity of [3H]citalopram was found to increase with increasing concentration of citalopram. This may be a homotropic positive allosteric effect, thus indicating the presence of an allosteric binding site for citalopram. The molecular weight of the proteins containing the high-affinity binding sites for citalopram and paroxetine, as well as the allosteric binding site for citalopram were determined by the irradiation method. The molecular weights of the three binding site proteins were found to be the same, suggesting that all three binding sites are located on the same protein molecule in the 5-HT transporter. The results support a hypothesis that the binding area for [3H]citalopram is located deeper in the transport channel than the [3H]paroxetine binding area. Thus the two high-affinity binding sites probably cover different, but overlapping, parts of the protein molecule. The allosteric binding site may be located elsewhere on the protein where it induces conformational changes of the 5-HT transporter with the result that high-affinity bound ligands get trapped in the transport channel, thereby explaining the increase in affinity.