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Identification of residues in the serotonin transporter engaged in high affinity recognition of antidepressants and cocaine

The serotonin (5HT) transporter (SERT) is an important target for antidepressants and psychostimulants, including cocaine and ecstasy. Using an evolutionary comparison of human and Drosophila SERTs, we have identified residues in transmembrane segments (TM) 1 and 3 that influence 5HT and competitor interactions. In TM 3, replacement of isoleucine at hSERT position 172 with methionine, the residue native to dSERT, discriminates between 5HT and antagonists, demonstrating no effect on substrate potency while causing a thousand‐fold loss of potency for citalopram, as well as significant losses in potency for several selective serotonin reuptake inhibitors, tricyclic antidepressants, and cocaine. Importantly, the reciprocal mutation in dSERT, M167I, shows a significant gain of potency for citalopram, fluoxetine and cocaine, but no change in 5HT uptake properties. hSERT I172 may coordinate citalopram binding with a previously identified TM 1 residue Y95, as hSERT Y95F/I172M shows a synergistic loss in citalopram potency.