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Séminaire - Guillaume SandozOptical probing and optogenetic of TREK channels physiology

Abstract :

Ion channels generate the electrical signals with which the nervous system uses to sense the world, process information, create memories and control behavior. One of the most diverse and important families of ion channels, the K2P channels, serves as a hub for the generation and regulation of the negative resting membrane potential and neuronal excitability. K2P channels also play a central role in the response of cells to diverse extracellular and intracellular signals, such as GPCR signaling, pH and membrane stretch.

The members of the TREK channel subfamily, TREK1, TREK2 and the more distantly-related TRAAK channel are widely expressed in the nervous system and are involved in several physiological and pathological functions, including pain perception, depression and PUFA-dependent neuroprotection against ischemia.  In this seminar, I will first describe the molecular basis for TREK1 and TREK2 channel pH-sensitivity and I will show how these channels can be oppositely regulated by pH.

Then, I will present single-molecule imaging data demonstrating that TREK channels can heteromultimerize to increase functional diversity, and I will discuss the development of a novel optical imaging method to probe interactions of a channel’s isolated intracellular domain with the plasma membrane. In the case of TREK, we showed that the interaction between the C-terminus and the plasma membrane is involved in the TREK channel gating and the regulation by GPCRs and the antidepressant fluoxetine.

Finally, and most interestingly, I will show you how we created light-gated versions of members of two K2P subfamilies and an important new method for optogenetics, which we call the photoswitchable conditional subunit method (TREK1-PCS), which makes it possible to endow native (unmodified) channels with light sensitivity. TREK1-PCS allows us to show that TREK1, typically considered to be only a leak channel, contributes actively to the hippocampal GABAB response which breaks with conventional idea that hippocampal GABAB is mediated only by GABAB-GIRK coupling. In addition, by using this tool we have shown how phospholipids act specifically on TREK channels and how small molecules, such as ethanol, can specifically modify TREK channel functions.

Selected publications

2014-1 Comoglio Y, Levitz J, Kienzler M, Lesage F, Isacoff EY and Sandoz G. PLD2 specifically regulates TREK channels via direct interaction and local production of phosphatidic acid. Proc Natl Acad Sci U S A 111; 13547-52

2014-2 Marion E, Song OR, Christophe T, Babonneau J, Fenistein D, Eyer J, Letournel F, Henrion D, Clere N, Paille V, Guérineau NC, Saint André JP, Gersbach P, Altmann KH, Stinear TP, Comoglio Y, Sandoz G, Preisser L, Delneste Y, Yeramian E, Marsollier L, Brodin P. Mycobacterial toxin induces analgesia in buruli ulcer by targeting the Angiotensin pathways. Cell. 157: 1565-76.

2012 Sandoz G, Levitz J, Kramer R & Isacoff EY. Optical control of endogenous proteins with a photo-switchable conditional subunit reveals a role for TREK1 in GABAB signaling. Neuron, 74; 1005-14.

2011 Sandoz G, Bell S & Isacoff E. Optical probing of a dynamic membrane interaction regulating TREK1 channel Proc Natl Acad Sci U S A, 2011, 8;108(6):2605-10.

2009 Sandoz G, Douguet D, Chatelain F, Lazdunski M & Lesage F, Extracellular acidification exerts opposite actions on TREK1 and TREK2 potassium channels via a single conserved histidine residue. Proc Natl Acad Sci U S A (2009) 106:14628-33.

2008 Sandoz G, Tardy M, Thümmler S, Feliciangeli S, Lazdunski M & Lesage F, Mtap2 is a constituent of the protein network that regulates TREK channel expression and trafficking. (2008) The Journal of Neuroscience, 28, 8545-8552.

2007 Feliciangeli S*, Bendahhou S*, Sandoz G*, Gounon P, Reichold M, Warth R, Lazdunski M, Barhanin J & Lesage F. Does sumoylation control K2P1 (TWIK1) background K+ channels? Cell, 130, 563-9.

Olivier Thoumine / Team Biophysics of Adhesion and Cytoskeleton/ Interdisciplinary Institute for Neuroscience UMR CNRS 5297 – University of Bordeaux (olivier.thoumine @

bio -sketch

Guillaume Sandoz (CR1 CNRS)
is head of the Biology of Ion Channels (BIC) at the institute of Biology Valrose (UMR7277 & Inserm-U1091). Guillaume Sandoz obtained is PhD in Neurosciences in 2003. After starting his career on the regulation of the pre-synaptic voltage-dependent calcium channels, he joined the Lazdunski Lab as a post-doc then as a “chargé de recherche” at the Institut of Cellular and Molecular Pharmacology in Nice (2004-2009), France, where he worked on the proteomic of K2P channels with the support of CNRS.  In 2009, Guillaume went as a Fulbright Visiting Scholar at the Isacoff lab, UC Berkeley. At Berkeley, Guillaume worked on several aspect of the K2P pharmacology then he determined the molecular mechanisms underlying the fluoxetine effect on K2P channels.  In 2012, he applied and has been selected to the ATIP-AVENIR program to start a new team called “Biology of Ion Channels” at the Institut of Biology Valrose (iBV) in Nice, France. The team is working on the physiology of K2P channels by using new optogenetic and single molecule techniques and on the regulation of TMEM16a chloride channels by partner proteins.