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ERC

gluactive Report Summary

Project ID: 647895
Funded under: H2020-EU.1.1.

Periodic Reporting for period 1 - gluactive (Activation Mechanism of a Glutamate Receptor)

Reporting period: 2015-07-01 to 2016-12-31

Summary of the context and overall objectives of the project

The project GluActive aims to elucidate the mechanisms of activation of AMPA type glutamate receptors, using functional, structural and computational approaches. This receptor is one of the most abundant in the brain of vertebrates. It is involved in all complex thought. Despite decades of work, bona-fide mechanisms that describe the activation states of this class of receptor are still lacking. It is important for society to understand the activation of glutamate receptors because this information will facilitate investigation of synapses, the acknowledged substrate of learning and memory in the brain. Further, because of their ubiquity, there may be some sense in which understanding the activation of glutamate receptors is useful in brain injury and disease.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Our major achievement to date is understanding the activation of the receptor by molecules that activate it weakly. When we consider the maximum activation of the receptor - being “on” all the time - we expect that the receptor adopts a certain geometry (or set of geometries) continuously. However, some molecules exist, called partial agonists, that bind to the receptor, but cause activation that is less than the maximum. These partial agonists can be synthetic, but some also occur in nature. A key question here, which we think relates to how the receptor works in a fundamental way, is why is the activation less than it could be? Is it because the receptor spends some of its time activated, and some time resting? In this interpretation, the receptor is somehow rigid its function and the agonist is bad at persuading it to activate, like a lazy runner who stops a lot. An alternative interpretation is that the partial agonists very effectively coax the receptor into a shape that is not very active. This idea is analogous to walking in a running race.

Which of these two competing ideas is the right answer for the AMPA receptor? We were able to measure the number of different geometries that the receptor can adopt for activators of different strengths. We could see that partial agonists that are bad at activating the receptor allow many different conformations to form. Partial agonists that cause about 50% activity are more selective. Therefore, perhaps unsurprisingly, the answer is that both theories are true. The different activators drive the receptor into overlapping sets of geometries, which they occupy for different amounts of time on average. The surprising point is that most of the arrangements are inactive. We think that this plethora of inactive states allows the receptor activation to be rapid and selective. This idea will be subject to further tests during the project GluActive. This work was a combined study of structural biology and functional experiments and is in press at Nature Communications.

Other aspects of the project are not yet at a mature enough stage to report publicly.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

With a novel combination of methods, including single molecule studies, we will investigate the AMPA-type glutamate receptor in unprecedented spatial and temporal detail. There is little wider socio-economic or societal impact, unforunately. Just an improved understanding of brain function at the molecular level.
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