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  • Neurotransmitter transporters are rapidly recycled

    2022-07-29

    Neurotransmitter transporters are rapidly recycled from and to the membrane. For instance, the GABA transporter GAT1 is recycled in a calcium and depolarization dependent manner. GAT1 located in the plasma membrane is internalized to a subpopulation of small vesicles different from the classical neurotransmitter-filled synaptic vesicles (Deken et al., 2003). Also the glycine transporter GLYT2 was found in a population of small vesicles mainly characterized by the presence of the recyclying endosomal marker Rab11 (Nuñez et al., 2009). The choline transporter, which belongs to a distint family of transporters, was found on presynaptic synaptic vesicles, and depolarization triggered an increase of the transporter in the plasma membrane, thus coupling the release of neurotransmitter and its reuptake (Ferguson et al., 2003).
    Materials and methods
    Results
    Discussion
    Acknowledgements We thank components of the confocal and electron microscope facilities of CBMSO, and to Enrique Núñez for their excellent technical assistance. This work was supported by Ministerio de Economia y Competitividad (Grant SAF2011-29961), Centro de Investigación Biomédica en Red de Enfermedades Raras (Intramural Project U-751), “Ramón y Cajal” Program (RYC-2010-06251, to B.C.) an institutional grant from the Fundación Ramón Areces.
    Introduction The benzophenanthridines are natural alkaloids abundant in certain plant species, which have been explored for centuries as active components of traditional folk medicines. Modern research has uncovered a significant potential for benzophenanthridines in the fights against microbes and cancer (Maiti and Kumar, 2010). Current research continues to reveal a plethora of new biological effects resulting from the interaction of these alkaloids with proteins and DNA however. The large interactive potential of these alkaloids is likely caused by their unique combination of the quarternary nitrogen, and polycyclic and planar structure interacting with the nucleophilic, aromatic and anionic moieties of ML355 (Schmeler et al., 1997). Benzophenanthridines exist in both positively charged and uncharged forms, in solution, traditionally named iminium (charged) and alkanolamine (uncharged). The equilibrium ratio of these forms is pH dependent (Maiti et al., 1983, Dostal et al., 1998). The reported pKa values for sanguinarine and chelerythrine (Maiti et al., 1983, Dostal et al., 1998, Absolinova et al., 2009), suggest that both alkaloid forms are present in vivo. Both iminium and alkanolamine alkaloid forms bind to protein molecules and influence numerous cellular functions. These include protein phosphorylation and dephosphorylation (Aburai et al., 2010, Herbert et al., 1990, Wang et al., 1997), apoptosis (Zhang et al., 2006), and proteolysis (Sedo et al., 2002). Sanguinarine also binds to the angiotensine AT1 receptor (Caballero-George et al., 2003) and suppresses angiogenesis (Eun and Koh, 2004). Sanguinarine has also been reported to inhibit a variety of enzymes including acetylcholinesterase, butyrylcholinesterase and choline acetyltransferase (Schmeller et al., 1997), perturb microtubule assembly (Lopus and Panda, 2006, Wolff and Knipling, 1993), and affect membrane permeability (Babich et al., 1996, Schmeller et al., 1997). We recently found that glycine transporter GlyT1 is also a target of benzophenanthridines, which show half maximal transporter inhibition in the low micromolar range (Jursky and Baliova, 2011). GlyT1 is a membrane protein, belonging to the family of sodium dependent neurotransmitter transporters (Kristensen et al., 2011). Several GlyT1 variants derived from a single gene have been identified (Borowsky et al., 1993, Kim et al., 1994, Smith et al., 1992). GlyT1 is highly abundant in the spinal cord, where it contributes to the regulation of the strychnine sensitive glycine inhibitory receptor. Lower abundance of GlyT1 can be found in the forebrain, where it limits the glycine concentration around the excitatory N-methyl-d-aspartate (NMDA) receptor (Gomeza et al., 2003, Rousseau et al., 2008, Sur and Kinney, 2007). Consequently, the impairment of GlyT1 might affect the higher neuronal functions regulated by the N-methyl-d-aspartate (NMDA) receptor (Sur and Kinney, 2007, Javitt, 2009, Mohler et al., 2011), NMDA mediated toxicity (Waxman and Lynch, 2005) and nociception (Dohi et al., 2009, Tanabe et al., 2008).