From Proteopedia

Dopamine Active Transporter

Dopamine Active Transporter (DAT) is a transmembrane protein found in human neurons, that is responsible for the reuptake of the neurotransmitter dopamine from the synapse back into synaptic vesicles for storage and later release. The action of this protein is responsible for the termination of signaling in dopaminergic pathways, which are responsible for many important biological functions such as cognition, motor control, sleep, and emotion.

Structure

DAT is a transmembrane protein that is made up of twelve transmembrane helices. LEUTAA, the bacterial homolog of monoamine transporters such as DAT, is also a transmembrane protein largely constituent of helices. The is illuminated on LEUTAA with the helices shown in orange and the sheets displayed in a red color. LEUTAA was chosen as a homologue due to the similar function and structure of the transporters, despite the low sequence homology. The clearly demonstrates the transmembrane nature of the protein, as intracellular fluid and extracellular fluid, shown in blue, have access to the top and bottom of the protein, but not the middle. Additionally, the pocket in which the sodium and substrate bind is illuminated by the few solvent molecules moving internally. When the are highlighted, with hydrophobic residues depicted in grey wireframe and hydrophilic represented in purple ribbon, it is again clear that LEUTAA is a transmembrane protein.

Function

Through the binding of two sodium represented in purple and the interacting residues shown in standard atomic color, dopamine can then bind after which the protein undergoes a conformational change to allow for the sodium and dopamine to enter the cell. Similar to other ionic pumps, the flow of sodium is coupled with the flow of a chlorine ion, represented in green, in order to balance the charge build up. The internalization of dopamine into neural cells allows for the clearing of dopamine from the synapse and the termination of dopamine signaling pathways. is being transported across the cell membrane by the LEUTAA transporter, shown here highlighted in yellow shown along side the interacting residues in standard atomic color and the two stabilizing sodium atoms.

Amphetamines

Amphetamines are a class of chemical compounds derived from amphetamine ((RS)-1-phenylpropan-2-amine) and are used both recreationally to induce euphoria and clinically to treat disorders, notably Attention Deficit Hyperactivity Disorder (ADHD). While amphetamines bear structural similarities to dopamine, they are not true competitive inhibitors of the dopamine transporter. Amphetamines instead work by binding to an unknown receptor that initiates phosphorylation of the N-terminus once Ca2+/calmodulin-dependent protein kinase II (CamKII) binds to the C-terminus. This causes DAT to conform to a "willing" conformation and results in DAT effluxing into the cell through the formation of an intercellular endosome. This reduces the expression of DAT in the surface of the cell membrane, reducing the rate at which dopamine is cleared from the synapse.