Project description
A paradigm shift in neuroscience and new therapeutic avenues
Understanding the brain’s complexities hinges on understanding G protein-coupled receptors (GPCRs), which are crucial for neural function and therapeutic strategies. Two decades ago, a revelation emerged – GPCR activity might be regulated by membrane potential shifts. Despite its potential significance, the intricate technical challenges involved obscured this phenomenon’s true nature. With this in mind, the ERC-funced GPCR Volt Dep Role project aims to decipher GPCR voltage dependence. Using the model organism Drosophila, researchers will employ a multidisciplinary approach, fusing electrophysiology, imaging, genetics, and behaviour analysis to illuminate how voltage controls GPCR function. Overall, the project is set to propel neuroscience into uncharted territory with potential therapeutic vistas.
Objective
G protein coupled receptors (GPCRs) are broadly expressed in the brain, mediate responses to many molecules, and are crucial for normal brain function and therapeutic intervention.
20 years ago, it was shown that the activity of many GPCRs is regulated by membrane potential. e.g. the activity of cholinergic M2R muscarinic and metabotropic glutamate mGluR3 receptors is reduced by depolarization, and that of M1R and mGluR1a is increased. However, due to high technical challenges, a crucial question remains unanswered: what are the physiological roles of this voltage dependency, its effect on neural activity, or its relevance to behaviour?
Recently, we showed that M1R voltage dependence is crucial for its recruitment. Not only that under physiological conditions, in vivo, M1R could not be activated without depolarization, depolarization alone was sufficient to activate M1R. Furthermore, flies with a voltage independent M1R had increased odor habituation indicating a paramount effect on behavior. These findings are pivotal in our thinking on GPCR recruitment and activity. However, to create a real paradigm shift, we need to unravel whether GPCR voltage dependence has a role in other types of GPCRs and neuronal processes.
The fly is an ideal model system to explore GPCR voltage dependence roles because it has a low variety of receptors with no functional overlap. In particular, the Drosophila dopaminergic and muscarinic receptors that are highly expressed in the olfactory system seem ideal.
I will use a multidisciplinary approach of electrophysiology, two-photon imaging, genetics, and behaviour to examine GPCR voltage dependency and means to manipulate it, unravel these GPCR physiological roles, and examine whether abolishing GPCR voltage dependence affects neuronal activity and behavioural output.
The understanding that there is a voltage rheostat that controls GPCR activity will open an entirely new field of research and can serve for new therapeutic intervention.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-ERC - HORIZON ERC Grants
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(opens in new window) ERC-2022-COG
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69978 Tel Aviv
Israel
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