New insights into ionotropic glutamate receptors in physiological and pathological conditions
- Autores: Federico Javier Miguez Cabello
- Directores de la Tesis: David Soto del Cerro (dir. tes.), Xavier Altafaj (codir. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2021
- Idioma: español
- Tribunal Calificador de la Tesis: José Antonio Esteban García (presid.), Núria Comes Beltran (secret.), José Manuel Fernández Fernandez (voc.)
- Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad de Barcelona
- Materias:
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- Resumen
New insights into ionotropic glutamate receptors in physiological and pathological conditions One of the most important families of ionotropic receptors are the glutamate receptors where the α-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) and the N-methyl-D-aspartate (NMDA) receptors (NMDARs) are principal members along with Kainate receptors. All three types are involved in excitatory synaptic transmission although their roles differ.
AMPARs are involved in the great majority of fast excitatory transmission playing a very important role in CNS communication. Besides, AMPARs are the effectors in plasticity processes, which are the cellular basis of learning and memory formation. AMPAR subunits are modulated by different transmembrane proteins that act as auxiliary subunits in neurons. Transmembrane AMPAR Regulatory Proteins (TARPs) are, amongst the different auxiliary subunits of the AMPARs described to date, the most important from a functional point of view. TARPs are highly and exclusively expressed in CNS with different temporal and regional expression. However, the role of the number of TARPs per AMPAR has not been deeply studied. During the thesis project it was studied how the stoichiometry AMPAR-TARP modulates the receptor. The AMPAR-TARP stoichiometry was explored in 2 different types of AMPAR, calcium permeable-AMPARs (CP-AMPARs) and calcium impermeable-AMPARs (CI-AMPARs). It has been found that not only the number of TARPs per receptor but also the position of the auxiliary subunit can play a role in AMPAR modulation. The results obtained show that different modulation of the AMPAR biophysical properties is achieved depending on the AMPAR-TARP stoichiometry as well as the AMPAR pharmacology. On the other hand, other proteins that interact with the AMPAR complex might be relevant in terms of AMPARTARP stoichiometry. It has been described that one of the many AMPAR interacting proteins, CPT1C, enhances AMPAR trafficking to cell membrane. Interestingly, it has been hypothesized that CPT1C could play a role in priming AMPAR with TARPs at the ER level, thus raising the possibility that CPT1C is determining AMPAR-TARP association although this idea has not been tested to date. The data obtained during this thesis project do not permit to confirm this hypothesis however, it cannot be discarded the possible role of CPT1C in AMPAR-TARP stoichiometry.
Another key ionotropic glutamate receptor type in neuronal physiology is the NMDAR. NMDARs are also tetrameric structures and they play a pivotal role in learning and memory. Since they are central players in neuronal physiology, a malfunction of NMDARs translates in significant complications for the organism. Indeed, they are involved in severe neurodevelopmental disorders due to mutations in the genes that codify for the different GluN subnunits (GRIN genes). Nowadays, next-generation sequencing technologies has permitted to uncover a high prevalence of GRIN mutations related with severe neurodevelopmental and psychiatric disease. De novo mutations affecting NMDARs can alter in different ways the receptor’s function. These is translated into a variable symptomatology among patients. An important part of this thesis was to characterise by electrophysiological approaches how different mutations modified the receptor properties. The different variants analysed were classified into gain or loss of function depending on their effect over total receptor current. There were characterized more than 20 GRIN variants to perform in a future personalized treatments for patients with the information obtained.
In total, all the work performed during this project permit to give new insights in the function of these two types of glutamate receptors in both physiological and pathological conditions.
