Structure, Function and Pharmacology of Neurotransmitter Reuptake Systems

The project investigates neurotransmitter transport systems, particularly the dopamine transporter (DAT) and neuronal glutamate transporter (EAAT3), and their roles in neuropsychiatric disorders and drug abuse. It employs cell biological, biochemical, physiological, and transcriptomic approaches to understand transporter function, regulation, and drug effects. Specific areas include: examining presynaptic actions of amphetamines, including activation of RhoA and Rac1 GTPases and internalization of DAT and EAAT3; investigating the role of the trace amine receptor TAAR1 as an intracellular target for amphetamines, MDMA, and other drugs, and its signaling through Gs and G13 proteins to activate PKA and RhoA; exploring mechanisms regulating EAAT3 trafficking to and from the cell surface after amphetamine treatment and its impact on glutamate clearance, using transgenic mouse and rat lines; identifying proteins associated with EAAT3 trafficking using proximity labeling (biotin ligase fusion) and mass spectrometry to define complexes and subcellular regulatory events; analyzing TAAR1 ligands, such as SEP-363856 (Ulotaront), for their effects on intracellular signaling in various neuronal cell types; and conducting transcriptomic analyses (RNA sequencing, ribosome tagging) of single nuclei from midbrain or actively translating ribosomes in DA neurons to identify genes (e.g., cholesterol metabolism genes) upregulated or downregulated by acute administration of AMPH or METH.