Saturday, 7th December 2019

Physiopathological aspects of glycine transporters in glycinergic neurotransmission: hyperekplexia and pain





Carmen Aragón







Research summary:

Current work involves the study of functional mechanism, biogenesis, intracellular trafficking, regulation of CNS glycinetransporters, GlyTs (GlyT1 and GlyT2), plasma membrane proteins of neurons and astrocytes responsible for the completion of glycinergic transmission. Gene deletion studies have suggested that modification of glycine transporter activity may be beneficial in treating several human disorders, including neuromotor deficiencies (startle disease, myoclonus), and neuropathic pain. Indeed, mutations in the gene encoding GlyT2 can cause hyperekplexia in humans and congenital muscular dystonia type 2 in calves.

Our recent studies have contributed to the identification of a site in the extracellular vestibule of GlyT2 involved in cation selectivity and glycine transport coupling mechanism by bioinformatics tools and directed mutagenesis (in collaboration with Dr. Antonio Morreale (Bioinformatic Unit, CBMSO).
We are also interested in the study of GlyT2 trafficking as a fundamental mechanism in the control of glycinergic activity as it provides a rapid manner to modulate its activity. In this regard we have defined molecular mechanisms underlying constitutive and PKC-regulated trafficking trough GlyT2 recycles between the cell surface and the cell interior and the role of membrane rafts and protein kinase C-dependent ubiquitination in the process.

In addition we have reported a coordinated regulation of GlyT1 and GlyT2 by P2Y1R that may result in an increase of the inhibitory pathways over the excitatory pathways leading to anti-nociception.

We have recently identified a new dominant mutation in theGlyT2genein eight patients of hyperekplexia. The heterologous expression and characterization of the mutation (Y705C) allowed us to determine changes in traffic kingand biochemical properties and maturation of the mutant transporter.


Fig01-300 --------- Fig02-300
Genetic and structural analysis of theY705C (GlyT2) mutant in hyperekplexia patiens. A, Partial sequences of exon 15 from control and patient 1 DNAs, respectively. B, Molecular model ofGlyT2 showing the localization of Tyr-705 in transmembrane domain 11 (TM11).  


Co-localization of GlyT2 wild type (A) and mutation of the C-terminal lysine cluster of GlyT2, 4KR (B) withsyntaxin1A and syntenin-1 in transfected hippocampal neurons. Hippocampal neurons were transfected with wild type GlyT2 or with the 4KR mutant at 10 DIV. The cultures were stained for GlyT2 syntaxin1A and syntenin-1 specific antibodies.



Relevant publications:

  • Giménez, C., Pérez-Siles, G., Martínez-Villarreal, J., Arribas-González, E., Jiménez, E.,  Núñez, E., de Juan-Sanz, J., Fernández-Sánchez, E., García-Tardón, N., Ibáñez, I., Romanelli, V., Nevado, J., James, V.M., Topf., M., Thomas, R.H., Desviat, L.R., Aragón, C., Zafra, F., Rees, M.I., Lapunzina, P., Harvey, R.J., and  López-Corcuera, B.  (2012). A novel dominant hyperekplexia mutation Y705C alters trafficking and biochemical properties of the presynaptic glycine transporter GlyT2". J. Biol. Chem. 287:28986-9002.
  • de Juan-Sanz, J, Núñez, E, López-Corcuera, B and Aragón, C. (2013) “Constitutive Endocytosis and Turnover of the Neuronal Glycine Transporter GlyT2 Is Dependent on Ubiquitination of a C-Terminal Lysine Cluster. PLoS ONE 8(3): e58863.
  • Arribas-González, E., Alonso-Torres, P., Aragón, C. and López-Corcuera, B. (2013). Calnexin-assisted biogenesis of the neuronal glycine transporter 2 (GlyT2). PLoS One. 8(5):e63230
  • de Juan Sanz, J., Núñez, E., Villarejo-López, L., Pérez-Hernández, D., Rodríguez-Fraticelli, A., López-Corcuera, B., Vázquez, J. and Aragón, C. (2013). Na+/K+-ATPase is a new interacting partner for the neuronal glycine transporter GlyT2 that down-regulates its expresión in vitro and in vivo. J Neurosci. 33:14269-81.



- Carmen Aragón. Académico Correspondiente de la Real Academia Nacional de Farmacia (9 de junio de 2011).

- Jaime de Juan-Sanz. Premio "Juan Abelló" (2012). Concurso científico anual de la Real Academia Nacional de Farmacia. Regulation of the glycinergic neurotransmission during inflammatory pain: A new pathway in the action of Prostaglandin E2 in the spinal cord. de Juan-Sanz, J., Núñez, E., López-Corcuera, B. and Aragón C.


Other activities:

- Pertenencia al Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, grupo U751) del Instituto de Salud Carlos III desde 2007.
- Pertenencia al Grupo de Investigación «Implicación de los SistemasGlicinérgico y Glutamatérgico en Patologías del Sistema Nervioso Central» (Jefe del grupo: Cecilio Giménez) perteneciente al Instituto de Investigación Biosanitaria IdiPAZ desde noviembre 2010.

Doctoral Theses:

Jaime de Juan Sanz (2013). Estudio del tráfico intracelular del transportador neuronal de glicina GlyT2: Modulación por lipid rafts, ubiquitinación e interacción con Na/K ATPasa. Universidad Autónoma de Madrid. Directores: Carmen Aragón Rueda y Beatriz López Corcuera.

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