Role of the human serotonin transporter external gate in substrate and antagonist recognition

Natalie R Sealover, Purdue University

Abstract

The serotonin transporter (SERT) is a twelve transmembrane (TMH) alpha helical protein that is responsible for the clearance of serotonin (5-HT) from the synaptic cleft. The regulation of serotonergic levels has been implicated in a number of disorders including depression and addiction. As such, SERT is the target of most antidepressants including the tricyclic antidepressants as well as several drugs of abuse including the amphetamines. However, the sites of interaction with SERT for the antidepressants and amphetamines have remained elusive. The purpose of these studies was to better understand the role of the internal and external gating residues in the mechanism of SERT action. A recently constructed homology model, coupled with mutagenesis data between human SERT (hSERT) and Drosophila SERT (dSERT) was used to determine a potential binding site for the tricyclic antidepressants and propose a mechanism for amphetamine-induced efflux at the transporter. Specifically, a region near extracellular loop (ECL) 2 that appears important for tricyclic antidepressant recognition was identified. The importance of a salt-bridge at the external gate in the ability of the transporter to efflux 5-HT in response to amphetamines was also determined.

Degree

Ph.D.

Advisors

Barker, Purdue University.

Subject Area

Neurosciences

COinS