InvestigatorJames Foster, Ph.D.

Location:  Department of Biomedical Sciences

Project Title:  Regulation of the dopamine transporter in health and disease

Description:  The neurotransmitter dopamine (DA) controls numerous processes including motor activity, emotion, and reward; and many diseases including Parkinson disease, depression, attention deficit hyperactivity disorder, schizophrenia, and drug abuse are related to abnormalities in dopaminergic function.  The plasmalemmal dopamine transporter (DAT) actively transports DA from the extracellular space into the presynaptic neuron, and is the primary mechanism controlling the concentration and duration of DA in the synaptic space.  Its activity is crucial for proper dopaminergic function, and dysregulation of its activity is hypothesized to contribute to dopaminergic disorders.  In addition, DAT is a major target for psychostimulant drugs such as cocaine and amphetamine (AMPH) which increase extracellular DA, the primary factor in the psychomotor stimulation and addictive effects of these drugs.  Therapeutic modulation of DA levels in mood and psychiatric disorders is also obtained through use of reuptake inhibitors such as methylphenidate (Ritalin) and Wellbutrin.  We have recently discovered that DAT is modified by S-palmitoylation, a post-translational modification in which C16 saturated palmitic acid is added to DAT via a thioester linkage to cysteine.  S-palmitoylation of integral membrane proteins confers a variety of properties including control of activity, trafficking, turnover, and subcellular targeting. Palmitoylation is reversible and dynamic, conferring the ability of the protein to respond to physiological signals and participate in regulatory processes in a manner analogous to phosphorylation.  In this project we are examining the role of palmitoylation in regulating DAT activity, subcellular trafficking, membrane microdomain localization, and degradation.