Neurotransmitter transporters, such as monoamine transporters (MATs), are membrane-bound proteins on the presynaptic terminal responsible for the reuptake of neurotransmitters from the synaptic cleft, thereby terminating the action of the neurotransmitter. Dopamine transporter (DAT), a member of the MAT family, is responsible for the reuptake of dopamine (DA). The MAT family displays ion (Na+, Cl-) dependence to drive transport and experimental evidence suggests that serotonin transporter (SERT) displays potassium ion (K+) dependence to reset the conformation of the protein. To date, there is no experimental evidence that suggests that K+ plays a similar role in DAT; however previous computational work shows K+ coordinating with residues on the intracellular side of DAT. The current work aims to discover the role of K+ in the transport cycle of DAT by examining computationally the interactions of K+ with the protein. A dual-bilayer system was employed, with DAT embedded in each membrane. DA was bound to the binding pocket of one protein, while the other protein was left in its apo state. Ions were added to the system to approximate physiological conditions, and the two intracellular baths were connected periodically to allow molecules to move more naturally. Based on our initial analysis, a single K+ is observed entering the apo DAT from the intracellular side. These observations suggest that the binding pocket is accessible from the intracellular side of the membrane and that the transport of K+ may be possible, if not necessary, for resetting the conformation of DAT.

Assessing the role of potassium in resetting the conformation of dopamine transporter

246th National Meeting (2013)

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