Hipótesis glutamatérgica de la esquizofrenia: mecanismos moleculares del transporte de glicina en las sinapsis glutamatérgicas
- Autores: Beatriz Cubelos, Cecilio Giménez, Francisco Zafra
- Localización: Anales de la Real Academia Nacional de Farmacia, ISSN-e 1697-4298, ISSN 0034-0618, Nº. 4 1, 2006, págs. 5-25
- Idioma: español
- Títulos paralelos:
- Glutamatergic hypothesis of schizophrenia: molecular mechanisms of glycine transport in glutamatergic synapses
- Enlaces
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Resumen
During the last few years, evidence has been obtained for a relationship between hypofunction of the NMDA type of glutamate receptor and schizophrenia. The glycine binding site on NMDAR and the glycine transporter GLYT1 represent some of the most promising therapeutic targets for developing new anti-schizophrenic drugs. Pharmacological inhibition of GLYT1 increases glycine levels in the surrounding of NMDAR and stimulates its function. Previous studies performed indicated that GLYT1 is physically associated with NMDAR, through the scaffolding protein PSD-95, due to the common interaction of both GLYT1 and NMDAR with PDZ domains of PSD-95. The objective of this research was centred on the study of the interaction of GLYT1 with other PDZ proteins, in special those that also interact with NMDAR. Particularly, we were interested the heteromeric tricomplex Mint-MALS-CASK. We analyzed the structural basis of these interactions and the functional consequence on GLYT1 in aspects such as the intracellular traffic, the turnover on the cell surface and the inclusion in specific microdomains of the membrane. In this way we analyzed the possible existence of common steps in GLYT1 and NMDAR processing. To do that we used molecular and cellular biology techniques, such as cotransfections in cellular systems of DNA constructs obtained by site directed mutagenesis and immunoprecipitations.
