The molecular mechanism for overcoming the rate-limiting step in monoamine neurotransmitter transport

Research output: Contribution to conferencePosterResearch

The monoamine transporter family consists of dopamine (DAT), norepinephrine (NET) and serotonin transporters (SERT) that mediate the reuptake of the monoamine neurotransmitters after their release during neurotransmission. These transporters play prominent roles in psychiatric disorders and are targets for drugs of abuse such as cocaine, amphetamine and ecstasy as well as anxiolytics and antidepressants.
The transporters undergo a series of concerted conformational changes in order to harness the driving force of co-transported cations to translocate the neurotransmitter across the neuronal membrane. The rate-limiting step in monoamine reuptake is the return of the empty transporter from an inward-facing to an outward-facing conformation without neurotransmitter and sodium bound. The molecular mechanism underlying this important conformational transition has not been described.
Crystal structures of the bacterial homolog, LeuT, captured in a new conformation without substrate or sodium bound shows a dramatic rotation of an absolutely conserved leucine into the substrate site. Molecular dynamics simulations combined with functional studies on SERT support that this leucine must act as an endogenous substrate mimic in the empty transporter in order for it to overcome the transition from the inward-facing to the outward-facing conformation. We also show that the local conformational changes associated with the rotation of this conserved leucine explains how cation sites are perturbed and reformed to ultimately drive vectorial transport of neurotransmitter.
Original languageEnglish
Publication year13 Jul 2016
Publication statusPublished - 13 Jul 2016
EventGordon Research Conferenc: Membrane Transport Proteins - Il Ciocco, Barga, Italy
Duration: 12 Jun 201616 Jun 2016
http://grc.org/programs.aspx?id=12736

Conference

ConferenceGordon Research Conferenc
LocationIl Ciocco
CountryItaly
CityBarga
Period12/06/201616/06/2016
Internet address

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