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Séminaire - Andrew PlestedSuperactivation of glutamate receptors by auxiliary proteins

Abstract :

Postsynaptic glutamate receptors found at synapses between nerve cells are essential for brain function. The activation of these complex macromolecular machines is triggered by neurotransmitters in a fraction of a second.

We identified a hotspot which controls both gating and their ability to follow fast signaling in a highly coupled fashion. This coupling was rather unexpected at the molecular level, but made sense in terms of signaling in the brain. This work generated tools that allowed us to investigate how glutamate receptor complexes incorporating auxiliary proteins are activated. Based on these experiments, we propose a simple activation mechanism with striking implications for short-term synaptic plasticity. In addition to investigating the activation of glutamate receptors, we have become interested in engineering receptors to be light sensitive, or to report their activity with a fluorescence signal. Various methods are available for inactivation of neuronal pathways, from knockouts to RNA interference and pharmacology.

All these methods are rather slow, which can make inference about mechanism difficult. We have achieved complete light-driven acute inactivation of glutamate receptors within a couple of seconds using genetically-encoded unnatural amino acids. This approach should be generally applicable to other receptors and proteins in native tissue.

Lab website: http://tinyurl.com/c4szuvm

 

Selected publications

Recent Publications

Klippenstein V, Ghisi V, Wietstruk M and Plested AJR (2014) Photoinactivation of glutamate receptors by a genetically encoded unnatural amino acid. Journal of Neuroscience 34:980-991

Lau AY, Salazar H, Blachowitz L, Ghisi V, Plested AJR, Roux B (2013) A conformational intermediate in glutamate receptor activation Neuron 79: 492-503

Miranda P, Contreras JE, Plested AJR, Sigworth FJ, Holmgren M, and Giraldez T (2013) State- dependent FRET reports calcium and voltage-dependent gating-ring motions in whole BK channels PNAS 110(13): 5217-22

Carbone AL and Plested AJR (2012) Coupled control of desensitization and gating by the ligand binding domain of glutamate receptors Neuron 74: 845–857

Scientific focus :

Our principal objective is to understand the relationship between the molecular structure of a given receptor (its shape) and its activity (what it does). We follow the notion that by understanding the receptors, we can understand the properties of the connections between nerve cells, and thus contribute to unraveling how the brain processes and stores information. The receptors themselves are also fascinating microscopic machines that, historically, have been full of interesting surprises.

Agenda