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Estudios sobre la localización y tráfico de los transportadores de las sinapsis glutamatérgicas SNAT2, SNAT5 y GLT1

AutorGonzález González, María Inmaculada
DirectorZafra Gómez, Francisco; Giménez Martín, Cecilio
Palabras claveSinapsis glutamatérgicas
Fecha de publicación2007
EditorUniversidad Autónoma de Madrid
ResumenProper function of glutamatergic neurotransmision implies the coordinate interplay of presynaptics, postsynaptic and glial cell elements. The chemical signal mediated by the neurotransmitter glutamate becomes an electric signal after the activation of different types of glutamate receptors. Another membrane proteins, glutamate transporters, clear the glutamate released into the synaptic cleft in order to avoid toxic levels for this neuroective substance. The high affinity glutamate transporter GLT1 is responsible for up to 90% of the glutamate uptake in the central nervous system. But glutamatergic synapses need additional transporters: glutamate inside glial cells is transformed into glutamine which is transferred back to presynaptic neurons to replenish neurotransmitter pools. This completes the glutamate-glutamine cycle. The transport of glutamine inside neurons might involve members on the neutral amino acid transporters that are classified in the SLC38 gene family, and named SNATs. Since the localization of SNAT2 and SNAT5 transporters in the nervous system is unknown, in this work we have studied the immunohistochemical distribution of both transporters. We have found the SNAT5 is expressed in glial cells that sourround gluatamatergic synapses, whilw SNAT2 is expressed in dendrites and axons, but not in terminals, of glutamatergic and glycinergic neurons. Additionally, we have studied the cellular localization of the GLT1b isoform of the glutamate transporter. We found that it is expressed in the postsynaptic elements of glutamatergic synapses. This localization is consistent with the interaction of GLT1b and the postsynaptic scaffold protein PSD95 that we also describe in the present work. This interaction occur through the GLT1b carboxyl terminal sequence motif that binds the first PDZ domain of PSD95, thereby permitting the formation of multiproteic complexes containing GLT1b, PSD95 and the NMDA subtype of glutamate receptor. Moreover, GLT1a could interact with this complex thanks to it capability to form oligomers with GLT1b. Finally, we have studied some aspects of the intracellullar traffic of GLT1 and we describe the important role played by the ubiquitin system in the regulation of this process. Thus, GLT1 biogenesis is regulated by the ERAD mechanism that eliminates in the proteasome the misfolded transporter molecules. In addition, ubiquitin is also involved in both, constitutive and regulated endocytosis of GLT1. We describe that the ubiquitin E3 ligase Nedd4.2 promotes ubiquitilation of GLT1 and regulate the lysosomal degradation of this protein. Also, ubiquitilation regulates the internalization of GLTT1 triggered by activation of the protein kinase C probably promoting the sorting of GLT1 into recycling vesicles
DescripciónTesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura 18-07-2007
Aparece en las colecciones: (CBM) Tesis
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