Bases moleculares de la esquizofrenia

Schizophrenia is a complex disorder that affects about 1% of the world population and is one of the most important causes of chronic disability. Although its etiology is unknown, the disease involves various morphologic and neurochemical abnormalities and it it’s accepted that genetic factors, either alone or enhanced by environmental and epigenetic factors play a role in its pathogenesis. Numerous studies over the last forty years have involved alterations in biogenic amines mediated neurotransmission, GABAergic and glutamatergic neurotransmission to the pathology of schizophrenic psychoses. Recently, the knowledge of susceptibility genes and proteins involved in the pathology of the disease, are allowing early diagnosis and the development of a new generation of compounds that can act as antipsychotics more selectively. La esquizofrenia es una enfermedad compleja que afecta a alrededor del 1% de la población mundial y constituye una de las más importantes causas de discapacidad crónica. Aunque su etiología es desconocida, la enfermedad implica diversas anomalías neuromorfológicas y neuroquímicas y se acepta que factores genéticos, bien solos o potenciados por factores ambientales y epigenéticos juegan un papel importante en su patogénesis. Numerosos estudios realizados durante los últimos cuarenta años han relacionado a alteraciones en la neurotransmisión mediada por aminas biógenas, la neurotransmisión glutamatérgica y gabaérgica con la patología de las psicosis esquizofrénicas. Recientemente, a través del conocimiento de genes de susceptibilidad así como de proteínas implicadas en la patología de la enfermedad, están permitiendo un diagnóstico precoz de la misma y el desarrollo de una nueva generación de compuestos que puedan actuar como antipsicóticos de una forma más selectiva.

Activity dependent internalization of the glutamate transporter GLT-1 requires calcium entry through the NCX sodium/calcium exchanger

GLT-1 is the main glutamate transporter in the brain and its trafficking controls its availability at the cell surface, thereby shaping glutamatergic neurotransmission under physiological and pathological conditions. Extracellular glutamate is known to trigger ubiquitin-dependent GLT-1 internalization from the surface of the cell to the intracellular compartment, yet here we show that internalization also requires the participation of calcium ions. Consistent with previous studies, the addition of glutamate (1 mM) to mixed primary cultures (containing neurons and astrocytes) promotes GLT-1 internalization, an effect that was suppressed in the absence of extracellular Ca. The pathways of Ca mobilization by astrocytes were analyzed in these mixed cultures using the genetically encoded calcium sensor GCaMP6f. A complex pattern of calcium entry was activated by glutamate, with a dramatic and rapid rise in the intracellular Ca concentration partially driven by glutamate transporters, especially in the initial stages after exposure to glutamate. The Na/Ca exchanger (NCX) plays a dominant role in this Ca mobilization and its blockade suppresses the glutamate induced internalization of GLT-1, both in astrocytes and in a more straightforward experimental system like HEK293 cells transiently transfected with GLT-1. This regulatory mechanism might be relevant to control the amount of GLT-1 transporter at the cell surface in conditions like ischemia or traumatic brain injury, where extracellular concentrations of glutamate are persistently elevated and they promote rapid Ca mobilization.This work was supported by grants from the Spanish MINECO (SAF2014- 55686-R) and the “Fundación Ramón Areces

Hipótesis glutamatérgica de la esquizofrenia: mecanismos moleculares del transporte de glicina en las sinapsis glutamatérgicas

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.Durante los últimos años, se han obtenido evidencias que relacionan la hipofunción del receptor de glutamato tipo NMDA (NMDAR) con la esquizofrenia. Los receptores NMDA necesitan para su estimulación la unión conjunta tanto de glutamato como de glicina, ya que ambos poseen en el receptor un sitio de unión específico. Puesto que la inhibición farmacológica de GLYT1 aumenta los niveles de glicina en los alrededores del receptor de glutamato tipo NMDA estimulando su función, el transportador de glicina GLYT1 representa una de las dianas terapéuticas más prometedoras para el desarrollo de nuevos fármacos antipsicóticos. Previamente hemos demostrado que GLYT1 se encuentra físicamente asociado con NMDAR a través de la proteína de adaptadora PSD-95 en neuronas glutamatérgicas. El objetivo de este trabajo se centra en el estudio de la interacción de GLYT1 con otras proteínas, especialmente con aquellas que también interaccionan con el 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 postsináptico. Puesto que GLYT1 interacciona simultáneamente con NMDAR y con el complejo Mint-MALS-CASK, proponemos que NMDAR y GLYT1 son cotransportados 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

Glycinergic transmission: glycine transporter GlyT2 in neuronal pathologies

Glycinergic neurons are major contributors to the regulation of neuronal excitability, mainly in caudal areas of the nervous system. These neurons control fluxes of sensory information between the periphery and the CNS and diverse motor activities like locomotion, respiration or vocalization. The phenotype of a glycinergic neuron is determined by the expression of at least two proteins: GlyT2, a plasma membrane transporter of glycine, and VIAAT, a vesicular transporter shared by glycine and GABA. In this article, we review recent advances in understanding the role of GlyT2 in the pathophysiology of inhibitory glycinergic neurotransmission. GlyT2 mutations are associated to decreased glycinergic function that results in a rare movement disease termed hyperekplexia (HPX) or startle disease. In addition, glycinergic neurons control pain transmission in the dorsal spinal cord and their function is reduced in chronic pain states. A moderate inhibition of GlyT2 may potentiate glycinergic inhibition and constitutes an attractive target for pharmacological intervention against these devastating conditions

Is eco-efficiency in greenhouse gas emissions converging among European Union countries?

Eco-efficiency refers to the ability to produce more goods and services with less impact on the environment and less consumption of natural resources. This issue has become a matter of concern that is receiving increasing attention from politicians, scientists and researchers. Furthermore, greenhouse gases emitted as a result of production processes have a marked impact on the environment and are also the foremost culprit of global warming and climate change. This paper assesses convergence in eco-efficiency in greenhouse gas emissions in the European Union. Eco-efficiency is assessed at both country and greenhouse-gas-specific levels using Data Envelopment Analysis techniques and directional distance functions, as recently proposed by Picazo-Tadeo et al. (Eur J Oper Res, 220:798–809, 2012). Convergence is then evaluated using the Phillips and Sul (Econometrica, 75:1771–1855, 2007) approach that allows testing for the existence of convergence groups. Although the results point to the existence of different convergence clubs depending on the specific pollutant considered, they signal the existence of at least four clear groups of countries. The first two groups are core European Union high-income countries (Benelux, Germany, Italy, Austria, the United Kingdom and Scandinavian countries). A third club is made up of peripheral countries (Spain, Ireland, Portugal and Greece) together with some Eastern countries (Latvia and Slovenia), while the remaining clubs consist of groups containing Eastern European countries

Bases Moleculares de la esquizofrenia

Schizophrenia is a complex disorder that affects about 1% of the world population and is one of the most important causes of chronic disability. Although its etiology is unknown, the disease involves various morphologic and neurochemical abnormalities and it it’s accepted that genetic factors, either alone or enhanced by environmental and epigenetic factors play a role in its pathogenesis. Numerous studies over the last forty years have involved alterations in biogenic amines mediated neurotransmission, GABAergic and glutamatergic neurotransmission to the pathology of schizophrenic psychoses. Recently, the knowledge of susceptibility genes and proteins involved in the pathology of the disease, are allowing early diagnosis and the development of a new generation of compounds that can act as antipsychotics more selectively.Peer Reviewe

Molecular bases of schizophrenia | Bases moleculares de la esquizofrenia

Schizophrenia is a complex disorder that affects about 1% of the world population and is one of the most important causes of chronic disability. Although its etiology is unknown, the disease involves various morphologic and neurochemical abnormalities and it it's accepted that genetic factors, either alone or enhanced by environmental and epigenetic factors play a role in its pathogenesis. Numerous studies over the last forty years have involved alterations in biogenic amines mediated neurotransmission, GABAergic and glutamatergic neurotransmission to the pathology of schizophrenic psychoses. Recently, the knowledge of susceptibility genes and proteins involved in the pathology of the disease, are allowing early diagnosis and the development of a new generation of compounds that can act as antipsychotics more selectively.Peer Reviewe

Metabolismo de la glucosa en hígado y cerebro de ratas con fenilcetonuria experimental

Tesis doctoral inédita de la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura:09-07-197