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BEATRIZ CUBELOS Y COLS. AN. R. ACAD. NAC. FARM.

receptor de glutamato tipo NMDA. Hemos encontrado que GLYT1 interacciona con
el tricomplejo heterotrimérico Mint-MALS-CASK. Este complejo está implicado en
el transporte polarizado del receptor del glutamato tipo NMDA al terminal postsi-
náptico. Puesto que GLYT1 interacciona simultáneamente con NMDAR y con el
complejo Mint-MALS-CASK, proponemos que NMDAR y GLYT1 son cotransporta-
dos al terminal sináptico, así en todo momento NMDAR puede ser regulado por
GLYT1. Estos resultados refuerzan la importancia de GLYT1 en la regulación de
NMDAR y su potencial como blanco de acción de fármacos antipsicóticos.

Palabras clave: Tráfico intracelular.—NMDAR.—Dominios PDZ.—Interacción
proteína-proteína.

ABSTRACT

Glutamatergic hypothesis of schizophrenia: molecular mechanisms of
glycine transport in glutamatergic synapses

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.

Key words: Intracellular traffic.—NMDAR.—PDZ domains.—Protein-protein
interactions.

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