The main goals of my 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.
We have 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. We are employing structure/function studies, molecular modeling and in silico virtual drug screens to pursue this hypothesis.
In an unrelated project, we have 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. We 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.
“Dopamine transport by the serotonin transporter: a mechanistically distinct mode of substrate translocation.”
Larsen MB, Sonders MS, Mortensen OV, Larson GA, Zahniser NR, Amara SG.
J Neurosci 27;31(17):6605-15 (2011)
“A catecholamine transporter from the human parasite Schistosoma mansoni with low affinity for psychostimulants.”
Larsen MB, Fontana AC, Magalhães LG, Rodrigues V, and Mortensen OV
Mol Biochem Parasitol. 177(1):35-41 (2011)
"Two allelic isoforms of the serotonin transporter from Schistosoma mansoni display electrogenic transport and high selectivity for serotonin"
Fontana AC, Sonders MS, Pereira-Junior OS, Knight M, Javitch JA, Rodrigues V, Amara SG, Mortensen OV
Eur J Pharmacol, 616(1-3):48-57 (2009)
"Genetic Complementation Screen Identifies a Map Kinase Phosphatase, MKP3, as a Regulator of Dopamine Transporter Trafficking"
Mortensen OV; Larsen MB; Prasad BM; and Amara SG
Mol Biol Cell 19(7):2818-29 (2008)
"Gain of function mutants reveal sites important for the interaction of the atypical inhibitors benztropine and bupropion with monoamine transporters"
Mortensen, OV; and Amara, SG
J Neurochem 98 (5):1531-40 (2006)