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Exposing nature’s view of ligand recognition in ionotropic glutamate receptors

Project description

Insight into ligand recognition by brain receptors

Ionotropic glutamate receptors (iGluRs) are transmembrane proteins in brain cells that bind the neurotransmitter glutamate and promote neural transmission at synapses. iGluRs mediate synaptic plasticity and our ability to learn and form memories. It is not possible to predict iGluR function based on the genetic code alone. The EU-funded iGLURs - A NEW VIEW project will collect phylogenetic and physiological information on iGluRs in different species and record the molecular changes that lead to ligand recognition. Moreover, the project will characterise the chemical interactions that determine the specific recognition of certain ligands by iGluRs.

Objective

Molecular biology strives for the prediction of function, based on the genetic code. Within neuroscience, this is reflected in the intense study of the molecular basis for ligand recognition by neurotransmitter receptors. Consequently, structural and functional studies have rendered a profoundly high-resolution view of ionotropic glutamate receptors (iGluRs), the archetypal excitatory receptor in the brain. But even this view is obsolete: we don’t know why some receptors recognize glutamate yet others recognize other ligands; and we have been unable to functionally test the underlying chemical interactions. In other words, our view differs substantially from nature’s own view of ligand recognition. I plan to lead a workgroup attacking this problem on three fronts. First, bioinformatic identification and electrophysiological characterization of a broad and representative sample of iGluRs from across the spectrum of life will unveil the diversity of ligand recognition in iGluRs. Second, phylogenetic analyses combined with functional experiments will reveal the molecular changes that nature employed in arriving at existing means of ligand recognition in iGluRs. Finally, chemical-scale mutagenesis will be employed to overcome previous technical limitations and dissect the precise chemical interactions that determine the specific recognition of certain ligands. With my experience in combining phylogenetics and functional experiments and in the use of chemical-scale mutagenesis, the objectives are within reach. Together, they form a unique approach that will expose nature’s own view of ligand recognition in iGluRs, revealing the molecular blueprint for protein function in the nervous system.

Host institution

UNIVERSITETET I BERGEN
Net EU contribution
€ 1 500 000,00
Address
MUSEPLASSEN 1
5020 Bergen
Norway

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Region
Norge Vestlandet Vestland
Activity type
Higher or Secondary Education Establishments
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Total cost
€ 1 500 000,00

Beneficiaries (2)