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Pierre Paoletti

Glutamate Receptors and Excitatory Synapses

The function of the human brain and its capacity for experience-dependent change hinges on the dynamics of chemical synapses. Our team has a long-standing interest in studying the molecular principles underpinning the structure and function of chemical synapses. Specifically, our research focuses on NMDA receptors (NMDARs), a family of glutamate-gated ion channel receptors that are essential mediators of synaptic plasticity and for which dysfunction is implicated in a broad range of neurosychiatric disorders, from schizophrenia to mental retardation and epilepsy.

We are interested in the structure, pharmacology and function of NMDARs. Using a multi-level approach, we aim at understanding the molecular operations of NMDARs, identifying their subunit-specific pharmacological properties, and deciphering the biological consequences of their functional diversity. We are also attempting to translate information about the regulation of receptor function into the design of novel therapeutic agents. To achieve these goals, we combine an array of advanced molecular, biophysical and physiological approaches, including receptor engineering, structural modelling, cellular electrophysiology, development of novel biosensors and optogenetic tools, and generation of genetically-modified ‘knock-out’ and ‘knock-in’ mice. Understanding the impact of NMDAR diversity and complexity on normal and diseased function remains a key challenge.

Zhu S, Stroebel D, Yao CA, Taly A and Paoletti P. Allosteric signaling and dynamics of the clamshell-like NMDA receptor GluN1 N-terminal domain. Nature Structural & Molecular Biology (2013), 20, 477-485.

Paoletti P, Bellone C and Zhou Q. NMDA receptor subunit diversity: impact of receptor properties, synaptic plasticity and disease. Nature Reviews Neuroscience (2013) 14, 383-400.

Vergnano AM, Rebola N, Savtchenko LP, Pinheiro PS, Casado M, Kieffer BL, Rusakov DA, Mulle C and Paoletti P. Zinc dynamics and action at excitatory synapses. Neuron (2014), 82(5), 1101-14.

Zhu S, Riou M, Yao CA, Carvalho S, Rodriguez PC, Bensaude O, Paoletti P*, Ye S*.
Genetically encoding a light switch in an ionotropic glutamate receptor reveals subunit-specific interfaces. PNAS (USA) 2014, 111(16):6081-6.
* Co-last author.

Klippenstein V, Hoppmann C, Ye S, Wang L, Paoletti P. Optocontrol of glutamate receptor gating and permeation by single side-chain photoisomerization. eLife (2017) 6, e25808.

Grand T, Abi Gerges S, David M, Diana MA, Paoletti P. Unmasking GluN1/GluN3A excitatory glycine NMDA receptors. Nature Communications (2018), 9(1):4769.

Esmenjaud J-B, Stroebel D, Chan K, Grand T, David M, Wollmuth L, Taly A, Paoletti P. An inter‐dimer allosteric switch controls NMDA receptor activity. EMBO Journal (2019), 0261-4189.

Paoletti P, CR Ellis-Davies G and Mourot A. Optical control of neuronal ion channels and receptors. Nature Reviews Neuroscience (2019), doi : 10.1038/s41583-019-0197-2.

Mony L and Paoletti P. Photocontrol of Metabotropic Glutamate Receptors: When One Agonist Is Not Enough, Make It Two. Neuron (2020) doi: 10.1016/j.neuron.2020.01.013.




Mechanism of long-distance allosteric transduction in NMDARs
Mechanism of long-distance allosteric transduction in NMDARs
Light-sensitive NMDARs using genetically-encoded unnatural AAs
Light-sensitive NMDARs using genetically-encoded unnatural AAs
Zinc action at excitatory synapses
Zinc action at excitatory synapses