Neurotransmitter transporters present at the cell surface are well-established as the primary targets for psychostimulant drugs of abuse and for drugs such as methylphenidate and amphetamines, which are used to treat attention deficit disorders. In recent studies, we have observed that once amphetamines enter neurons they can activate multiple intracellular signaling pathways. Within the cell amphetamines activate the small GTPases, Rho and Rac1, and trigger endocytosis of the dopamine transporter (DAT) and a neuronal glutamate transporter (EAAT3) by a RhoA-dependent internalization pathway. These events depend upon the expression of an intracellular G-protein coupled trace amine receptor (TAAR1) that couples to at least two types of G-protein alpha-subunit within the cell. Using a series of subcellularly-targeted genetic FRET sensors to detect RhoA or PKA activation, we have been able to characterize the subcellular membrane compartments where TAAR1 signaling events initiate. These results imply that amphetamine-like drugs not only inhibit monoamine transport and potentiate neurotransmitter action, but they also activate signaling pathways through their direct action on an intracellular GPCR target. This lecture will highlight the major signaling pathways that modulate dopamine transporter function and will consider how these regulatory events can be linked to the elegant conformational models that were a focus of Professor Jeffry Madura’s work.

Dynamic regulation of signaling pathways in dopamine neurons: the intracellular actions of amphetamines

256th National Meeting (2018)

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