Molecular and cellular biology of neurotransmitter transporters.

Neurotransmitter transporters present on the plasma membrane contribute to the clearance and recycling of neurotransmitters and can have a profound impact on the extent of receptor activation during neuronal signaling. Our major research efforts have focused on the structure, regulation and cellular physiology of two families of sodium-dependent neurotransmitter transporters: the biogenic amine and the excitatory amino acid carriers. The dopamine, norepinephrine and serotonin transporters (DAT, NET and SERT) are well-established targets for addictive drugs including cocaine and amphetamines, and for therapeutic antidepressants. Electrophysiological approaches and imaging techniques have been used to examine the impact of psychostimulant drugs on the signaling properties, physiology and acute regulation of the DAT in cultured midbrain dopamine neurons. In humans, clearance of the major excitatory amino acid neurotransmitter, glutamate, is mediated by five different subtypes of excitatory amino acid transporters (EAATs1-5) found in specific regions of neurons and glial cells. Although these carriers limit CNS concentrations of glutamate, they also possess a ligand-gated chloride channel activity that can regulate neuronal excitability. Our work continues to use molecular genetic, electrophysiological and cell biological approaches to explore the relationships between neurotransmitter transporter structure, substrate transport, inhibitor binding and ion permeation.

Sample Publications:

Mortensen OV, Larsen MB, Prasad BM, Amara SG. Genetic Complementation Screen Identifies a Mitogen-activated Protein Kinase Phosphatase, MKP3, as a Regulator of Dopamine Transporter Trafficking. Mol Biol Cell. 2008 Jul;19(7):2818-29.

Amara SG. Chloride finds its place in the transport cycle. Nat Struct Mol Biol. 2007 Sep;14(9):792-4.

Fontana AC, de Oliveira Beleboni R, Wojewodzic MW, Ferreira Dos Santos W, Coutinho-Netto J, Grutle NJ, Watts SD, Danbolt NC, Amara SG. Enhancing glutamate transport: mechanism of action of Parawixin1, a neuroprotective compound from Parawixia bistriata spider venom. Mol Pharmacol. 2007 Nov;72(5):1228-37.

Torres GE, Amara SG. Glutamate and monoamine transporters: new visions of form and function. Curr Opin Neurobiol. 2007 Jun;17(3):304-12. Epub 2007 May 16.

Mortensen OV, Amara SG. Gain of function mutants reveal sites important for the interaction of the atypical inhibitors benztropine and bupropion with monoamine transporters. J Neurochem. 2006 Sep;98(5):1531-40.

Leighton BH, Seal RP, Watts SD, Skyba MO, Amara SG. Structural rearrangements at the translocation pore of the human glutamate transporter, EAAT1. J Biol Chem. 2006 Oct 6;281(40):29788-96. Epub 2006 Jul 28.

Cheng C, Glover G, Banker G, Amara SG. A novel sorting motif in the glutamate transporter excitatory amino acid transporter 3 directs its targeting in Madin-Darby canine kidney cells and hippocampal neurons. J Neurosci. 2002 Dec 15;22(24):10643-52.

Ingram SL, Prasad BM, Amara SG. Dopamine transporter-mediated conductances increase excitability of midbrain dopamine neurons. Nat Neurosci. 2002 Oct;5(10):971-8.

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