Thomas Stockner, Medical University of Vienna

Characterising the structure-function relationship of the SLC6 transporter family

Host: Eurico Cabrita, UCIBIO at FCT NOVA

Abstract

The secondary active transporters of the solute carrier 6 (SLC6) family use the transmembrane chemical potential of sodium to energise substrate transport across the cell membrane. The most prominent members of the SLC6 family are the neurotransmitter transporter for dopamine, serotonin, nor-adrenaline and γ-aminobutyric acid (GABA). These transporter are widely expressed throughout the brain. Their role of is to terminate neurotransmission by fast removal of the neurotransmitters from the synaptic cleft. Abnormal transporter function is associated with different disease states such as addiction, anxiety disorders, depression, or bipolar disorder, or seizure. Several drugs used for the treatment of these disease target NSS, while a number of drugs of abuse, including cocaine or ecstasy interfere with normal NSS transporter function.

Biochemical, biophysical and pharmacological data together with crystal and cryoEM structures indicate that SLC6 family member us alternating for substrate transport, whereby sodium and possibly chloride bind first to an outward facing conformation of the transporter, followed by ligand binding that trigger substrate translocation, which gets released to cytosol together with the co-transported ions. I will be presenting biochemical, pharmacological, biophysical data together with molecular modelling and advanced simulations data to directly investigate the structural, dynamics, and energetic aspects of substrate transport and elucidate on the key aspects of the transport cycle.