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    Neurotransmitter transporters - a clinically relevant target of psychostimulant drugs

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    Séminaire Institut Cochin

    Lundi 16 décembre 2019 - 14h00 - Salle de réunion Méchain 1, 1er étage

     


    Harald Sitte

    Professor at the Center for Physiology and Pharmacology
    (Institute of Pharmacology), Vienna, Austria

     

     invité par Ralf Jockers

    Institut Cochin, 22 rue Méchain, 75014 Paris

     

    Résumé

    Neurotransmitters transporters are located in presynaptic specializations. They inactivate neurotransmitter-mediated neurotransmission following exocytotic release by a simple reuptake mechanism. Recent crystallographic examination of bacterial homologs to mammalian neurotransmitter transporters provides a structural scaffold which supports transport by an alternative access mechanism. Monoamine transporters are a target of clinically relevant drugs: (i) antidepressants competitively block the reuptake of monoamines. Thereby, these compounds enhance the extracellular monoamine concentration which is relevant for clinical success. (ii) amphetamines and cathinones, which behave as substrates of the transporters, trigger non-exocytotic neurotransmitter release (efflux). The exact molecular mechanism of the psychostimulant action, however, still remains enigmatic.

     

    Quelques publications

    1. Buchmayer, F. et al., 2013. Amphetamine actions at the serotonin transporter rely on the availability of phosphatidylinositol-4,5-bisphosphate. Proceedings of the National Academy of Sciences, 110(28), pp.11642-11647. Available at: http://dx.doi.org/10.1073/pnas.1220552110.
    1. Amphetamine action at the cocaine- and antidepressant-sensitive serotonin transporter is modulated by αCaMKII. Steinkellner T, Montgomery TR, Hofmaier T, Kudlacek O, Yang JW, Rickhag M, Jung G, Lubec G, Gether U, Freissmuth M, Sitte HH. J Neurosci. 2015 May 27;35(21):8258-71. doi: 10.1523/JNEUROSCI.4034-14.2015.
    2. Fluorinated phenmetrazine "legal highs" act as substrates for high-affinity monoamine transporters of the SLC6 family. Mayer FP, Burchardt NV, Decker AM, Partilla JS, Li Y, McLaughlin G, Kavanagh PV, Sandtner W, Blough BE, Brandt SD, Baumann MH, Sitte HH. Neuropharmacology. 2018 May 15;134(Pt A):149-157. doi:10.1016/j.neuropharm.2017.10.006. Epub 2017 Oct 6.
    3. An unsuspected role for organic cation transporter 3 in the actions of amphetamine. Mayer FP, Schmid D, Owens WA, Gould GG, Apuschkin M, Kudlacek O, Salzer I, Boehm S, Chiba P, Williams PH, Wu HH, Gether U, Koek W, Daws LC, Sitte HH. Neuropsychopharmacology. 2018 Nov;43(12):2408-2417. doi: 10.1038/s41386-018-0053-5. Epub 2018 Apr 6.
      1. para-Trifluoromethyl-methcathinone is an allosteric modulator of the serotonin transporter. Niello M, Cintulova D, Hellsberg E, Jäntsch K, Holy M, Ayatollahi LH, Cozzi NV, Freissmuth M, Sandtner W, Ecker GF, Mihovilovic MD, Sitte HH. Neuropharmacology. 2019 Apr 24:107615. doi: 10.1016/j.neuropharm.2019.04.021.
    1. Sitte, H.H. & Freissmuth, M., 2015. Amphetamines, new psychoactive drugs and the monoamine transporter cycle. Trends in Pharmacological Sciences, 36(1), pp.41-50. Available at: http://dx.doi.org/10.1016/j.tips.2014.11.006.
    2. Sandtner, W. et al., 2015. Binding Mode Selection Determines the Action of Ecstasy Homologs at Monoamine Transporters. Molecular Pharmacology, 89(1), pp.165-175. Available at: http://dx.doi.org/10.1124/mol.115.101394.
    3. Anderluh, A. et al., 2017. Direct PIP2 binding mediates stable oligomer formation of the serotonin transporter. Nature Communications, 8, p.14089. Available at: http://dx.doi.org/10.1038/ncomms14089.

     

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