Innovating Works

DynamiK

Financiado
Exploring the role of NMDA receptors in K+ channel nanoscale organisation, surfa...
Exploring the role of NMDA receptors in K+ channel nanoscale organisation, surface dynamics and function NMDA glutamate receptors (NMDAR) are undisputed key players in synaptic plasticity, a role that has been attributed to their calcium permeability. It emerged over the past decade that the membrane trafficking and nanoscale organiz... NMDA glutamate receptors (NMDAR) are undisputed key players in synaptic plasticity, a role that has been attributed to their calcium permeability. It emerged over the past decade that the membrane trafficking and nanoscale organization of NMDARs also plays a major role in synaptic adaptation. This was further substantiated by the discovery that patients’ autoantibodies targeting NMDARs (NMDAR-Abs) induce major psychiatric and neurological symptoms through compromised NMDAR surface trafficking but intact ionotropic function. NMDAR-Abs rapidly alter NMDAR membrane dynamics by disrupting their interaction with specific interactors whose membrane organization and function are also possibly corrupted. Herein, I hypothesize that the whole surface interactome of NMDARs, which is still poorly defined, is altered by NMDAR-Abs, explaining the complex neuropsychiatric presentation observed in NMDAR-Ab-positive patients. To tackle this, I will perform an unbiased proximity labelling approach coupled to quantitative proteomics to provide the first identification of the NMDAR surface interactome in hippocampal neurons, and determine how it is altered by patients’ NMDAR-Abs. Among the targets, the potassium K+ channels, which tightly control neuronal excitability, are of prime interest since they functionally interact with NMDARs, and preliminary evidence from the host laboratory show that NMDAR-Abs alter hippocampal neuron excitability. Using super-resolution microscopy and electrophysiology, I will test whether NMDAR-Abs modulate the membrane trafficking and nanoscale topography of K+ channels, impairing K+ channel currents. Genetic or pharmacological modulation will be used to question the membrane interplay between NMDARs and K+ channels in a pathological, as well as basal, context. This original proposal will thus shed new light on the NMDAR membrane interactome, its dynamics at the nanoscale, and implication in a severe neurological and psychiatric autoimmune paradigm. ver más
30/09/2025
CNRS
196K€
Perfil tecnológico estimado
Duración del proyecto: 28 meses Fecha Inicio: 2023-05-04
Fecha Fin: 2025-09-30

Línea de financiación: concedida

El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2023-05-04
Línea de financiación objetivo El proyecto se financió a través de la siguiente ayuda:
HORIZON-MSCA-2022-PF-01-01: MSCA Postdoctoral Fellowships 2022
Cerrada hace 2 años
Presupuesto El presupuesto total del proyecto asciende a 196K€
Líder del proyecto
CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE... No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico TRL 4-5