Possible Existence of Quaternary Structure in the High-Affinity Serotonin Transport Complex

Abstract Deletion-mutants of the cloned mouse serotonin transporter (SERT) rendered dominant negative-mutant effects upon wild-type transporter activities in heterologous expression studies; such effects were transporter-selective and did not influence the activities of co-expressed neuronal GABA transporter. Heterologous expression of linear concatenates (up to four copies) of SERT further revealed discernable uptake activities for both transporter-dimer and -tetramer, but not for the trimer. Kinetic and pharmacological analyses revealed that the monomer, dimer, and tetramer manifested comparable transport K m and potencies for known serotonin uptake inhibitors; the tetramer was distinct from the others only in manifesting notably reduced transport V max . Surprisingly, equivalent cocaine congener-binding activities were observed for all concatenates, including the functionally inactive trimer. These findings collectively support the existence of quaternary structure in the active 5-HT transport complex; such structure is likely to be a critical determinant of ligand transport activities, but apparently not of transporter–inhibitor interactions.