Neurotransmitter transporters, drug addiction and affective disorders

The main goals of Dr. Mortensen's research are focused on enhancing our understanding of how drugs of abuse, antidepressants and other small molecules interact with and modulate the function of monoamine transporters, including the serotonin transporter (SERT), the dopamine transporter (DAT), and the norepinephrine transporter (NET).

DAT, NET, and SERT are the primary mechanism for clearance of their respective neurotransmitter from the extracellular space. They are targets of psychostimulants, such as cocaine and amphetamines, and of antidepressants such as SSRIs.

Dr. Mortensen's lab has recently isolated SERT and DAT cDNAs from the human parasite Schistosoma mansoni. The uptake kinetics for serotonin are indistinguishable between human and parasite SERT but the parasite SERT and DAT displays dramatically reduced affinity for amphetamines and several inhibitors including cocaine and SSRIs. These results suggest that subtle structural differences between the parasite and human carrier exist that determine exogenous substrate and inhibitor interactions and these differences, if identified, can be employed as templates to design targets of transporter modulating molecules. The lab is employing structure/function studies, molecular modeling and in silico virtual drug screens to pursue this hypothesis.

In an unrelated project, Dr. Mortensen's lab has demonstrated that the MAP kinase phosphatase 3 (MKP3) modulates DAT surface expression, voltage gated calcium channel expression, and neurotransmitter release. Taken together, this points to a role of MKP3 in controlling neurotransmitter homeostasis. They are investigating how this central regulator of MAP kinase signaling contributes to various disease states of the brain including drug addiction, psychiatric disorders, and neurodegenerative diseases such as Parkinson's, Alzheimer's and Huntington's.

Source:  https://drexel.edu/medicine/faculty/profiles/ole-mortensen/