Intracellular loop 5 is important for the transport mechanism and molecular pharmacology of the human serotonin transporter

Research output: Contribution to conferencePosterResearch

The serotonin transporter (SERT) belongs to a family of transport proteins called the neurotransmitter:sodium
symporters. The specialized members of this family transport different neurotransmitters across the cell
membrane, thereby regulating signaling between neurons. Most of these transporters are important drug
targets in treating i.e. affective disorders such as depression and anxiety, and for drugs of abuse such as
ecstasy and cocaine.
The normal function of the SERT relies on large conformational changes and its inhibition by antidepressants
represents a conformational lock. Understanding the molecular mechanism of inhibition and which structural
elements are involved in inhibitor binding and conformational changes of the transporter will provide clues for
the development of improved drugs for the treatment of depression.
Guided by our previous studies, we combined different biochemical methods to characterize the interplay
between TM10-IL5-TM11 region and the rest of the SERT protein in response to inhibitor and substrate
binding and as well as the conformational changes in SERT. We find that the length of IL5 affects the
conformational equilibrium of SERT and increases the turn-over rate of SERT for 5-HT transport. We also find
that the potency of antidepressants is improved by in SERT with a lengthened IL5. These findings support the
notion that intracellular loops are important substructures with a role in both the transport mechanism and
molecular pharmacology of SERT.
Original languageEnglish
Publication year7 Sep 2015
Publication statusPublished - 7 Sep 2015

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