Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties.

Genetic and bioinformatic analyses have identified missense mutations in GRIN2B encoding the NMDA receptor GluN2B subunit in autism, intellectual disability, Lennox Gastaut and West Syndromes. Here, we investigated several such mutations using a near-complete, hybrid 3D model of the human NMDAR and studied their consequences with kinetic modelling and electrophysiology. The mutants revealed reductions in glutamate potency; increased receptor desensitisation; and ablation of voltage-dependent Mg block. In addition, we provide new views on Mg and NMDA channel blocker binding sites. We demonstrate that these mutants have significant impact on excitatory transmission in developing neurons, revealing profound changes that could underlie their associated neurological disorders. Of note, the NMDAR channel mutant GluN2B unusually allowed Mg permeation, whereas nearby N615I reduced Ca permeability. By identifying the binding site for an NMDAR antagonist that is used in the clinic to rescue gain-of-function phenotypes, we show that drug binding may be modified by some GluN2B disease-causing mutations

Andean Microbial Ecosystems: Traces in Hypersaline Lakes About Life Origin

High-altitude Andean lakes (HAALs) represent unique environments on the Earth where one can study the biological chemistry of life in one of its most extreme versions. The Atacama Desert, Argentine Puna, and Bolivian Altiplano harbor hypersaline lakes where polyextremophilic Andean Microbial Ecosystems (AMEs) inhabit microbial mats, evaporitic mats, biofilms (BF), evaporites (EV), and microbialites (Mi). These AMEs have two remarkable characteristics: (i) they are the only ones in the world that inhabit areas ranging from 3100 to 4200 masl; and (ii) they are excellent modern analogues of those which populated the primitive Earth ~3 billion years ago. In this chapter, we will delve into the different kinds of AMEs present in the HAAL, their formation, structure, and their adaptation to conditions largely influenced by volcanic activity, UV radiation, arsenic content, high salinity, low dissolved oxygen content, extreme daily temperature fluctuation, and oligotrophic conditions. All of these physicochemical parameters recreate the early Earth and even extraterrestrial conditions. The relevance of studying these ecosystems does not lie only in scientific-descriptive and/or economic interest. The scientific research community has a great responsibility to address climate change. In this scenario, the AMEs could have played a key role, influencing changes that allowed the origin of aerobic life and those who have faced the great climatic events of the Earth.Fil: Saona Acuña, Luis Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Planta Piloto de Procesos Industriales Microbiológicos; ArgentinaFil: Soria, Mariana Noelia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Planta Piloto de Procesos Industriales Microbiológicos; ArgentinaFil: Villafañe, Patricio Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Planta Piloto de Procesos Industriales Microbiológicos; ArgentinaFil: Lencina, Agustina Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Planta Piloto de Procesos Industriales Microbiológicos; ArgentinaFil: Stepanenko, Tatiana Mariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Planta Piloto de Procesos Industriales Microbiológicos; ArgentinaFil: Farias, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Planta Piloto de Procesos Industriales Microbiológicos; Argentin