H2020Индивидуална стипендия2018–2020

KARhet · Molecular architecture of heteromeric kainate receptor complexes

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2018-06-18 → 2020-06-17
Финансиране от ЕС: 183 455 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Каинатните рецептори в мозъка и начинът, по който се свързват с други протеини, се анализират на молекулярно ниво. По-доброто разбиране на тези структури помага при разработването на лекарства срещу епилепсия и разстройства на настроението.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Molecular architecture of heteromeric kainate receptor complexes

The mammalian nervous system is a complex network containing many types of cells, each playing a specific role in the transmission of information. The main excitatory neurotransmitter is L-glutamate, mediating fast neurotransmission through ionotropic glutamate receptors (iGluRs), which are divided into three sub-families: NMDA, AMPA and KA receptors. While AMPA and NMDA receptors have a prominent and well-characterised role in fast excitatory transmission, KA receptors (KARs) are modulators of synaptic circuits. In the native context, KARs rely on heteromeric assembly and binding partners for their proper function. Indeed, the most abundant KARs are thought to be formed of the two subunit subtypes, GluK2 and GluK5. Heteromeric assembly of these subunits endows synaptic KARs with unique biophysical and pharmacological properties. Moreover, these receptors associate with auxiliary proteins at both pre- and postsynaptic membranes and this influences their trafficking, clustering and functional properties; detailed structural information regarding these complexes still remains to be determined. KARs have been associated with disorders of the central nervous system such as mood disorders and temporal-lobe epilepsy. Given their role as neuronal circuit modulators, they represent an important potential pharmacological target, especially compared to AMPA and NMDA receptors, whose roles in synaptic transmission and plasticity are crucial. However, this requires a deeper understanding of synaptic KAR assemblies. The overall aim of this project was to investigate the rules of assembly of KAR complexes in structural terms, including specific interactions between subunits in a heteromeric complex, as well as those between the receptors and their binding partners. Using single-particle cryo-electron microscopy (cryo-EM), this project provides a first and preliminary insight into the rules of assembly of a synaptic KAR complex.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Kainate receptors (KARs) are glutamate-gated ion channels (iGluRs) known as neuronal circuit modulators. Because of their involvement in epilepsy and mood disorders, they represent an important pharmacological target. Over the past decade, we have learned a lot about synaptic KARs, but their assembly, function and pharmacology remain elusive compared to the closely-related alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). During my PhD, I used electrophysiology to study the functional properties of KARs and AMPARs associated with auxiliary proteins to gain insights into their roles at neuronal synapses.In the proposed research project, I plan to use structural methods such as X-ray crystallography and single-particle cryo-electron microscopy and tomography to address the questions brought by my PhD thesis work. Specifically, I will combine the functional knowledge and skills that I have acquired with the structural expertise of the host laboratory to inquire about the structural assembly of synaptic KARs and especially the interactions between the different KAR subunits and their synaptic binding partners. Combined with the functional analysis of these interactions, this work will provide valuable information for a deeper understanding of synaptic complexes at the molecular level.

Оригинален текст от CORDIS (на английски).

Участници

UNITED KINGDOM RESEARCH AND INNOVATION · SWINDONКоординаторОбединеното кралство