Abstract
Neurotransmitter sodium symporters (NSS) are a subfamily of SLC6 transporters responsible for regulating neurotransmitter signalling. They are a major target for psychoactive substances including antidepressants and drugs of abuse, prompting substantial research into their modulation and structure-function dynamics. Recently, a series of allosteric transport inhibitors have been identified, which may reduce side effect profiles, compared to orthosteric inhibitors. Allosteric inhibitors are also likely to provide different clearance kinetics compared to competitive inhibitors and potentially better clinical outcomes. Crystal structures and homology models have identified several allosteric modulatory sites on NSS including the vestibule allosteric site (VAS), lipid allosteric site (LAS) and cholesterol binding site (CHOL1). Whilst the architecture of eukaryotic NSS is generally well conserved there are differences in regions that form the VAS, LAS, and CHOL1. Here, we describe ligand-protein interactions that stabilize binding in each allosteric site and explore how differences between transporters could be exploited to generate NSS specific compounds with an emphasis on GlyT2 modulation.
Highlights
Neurotransmitter sodium symporters (NSS) are secondary active transporters that regulate synaptic concentrations of neurotransmitters via reuptake into surrounding glial cells or presynaptic terminals
The mechanism of transport has largely been inferred from crystal structures of the Aquifex aeolicus bacterial leucine transporter (LeuT) and supplemented by recently solved structures of the eukaryotic Drosophila melanogaster dopamine transporter, human serotonin and human glycine transporter type 1 (Yamashita et al, 2005; Penmatsa et al, 2013; Wang et al, 2015; Coleman et al, 2016; Shahsavar et al, 2021)
Whilst the principles will be derived from various family members, we will focus on the glycine transporter GlyT2 as a drug target
Summary
Neurotransmitter sodium symporters (NSS) are secondary active transporters that regulate synaptic concentrations of neurotransmitters via reuptake into surrounding glial cells or presynaptic terminals. Members of the solute carrier 6 (SLC6) family act on a broad range of neurotransmitter substrates: glycine (GlyTs), dopamine (DAT), serotonin (SERT), noradrenaline (NET) and γ-aminobutyric acid (GABA, GAT) (Amara and Kuhar, 1993; Kristensen et al, 2011). Impaired functions of these transporters have been implicated in a variety of neurological disorders including addiction, depression, epilepsy, hyperekplexia, neuropathic pain, Parkinson’s disease, and schizophrenia (Benarroch, 2011; Benarroch, 2013). Whilst the principles will be derived from various family members, we will focus on the glycine transporter GlyT2 as a drug target
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