SANDOZ

Guillaume SANDOZ

Biology of ion channels

Main interests

Scientific Questions

Ion channels generate the electrical signals with which the nervous system senses the world, processes information, creates memories and controls behavior. One important family of ion channels, the K2P family, serves as a hub for the generation and regulation of the negative resting membrane potential and neuronal excitability. They have been shown to be involved in several physiological and pathophysiological functions such as depression and migraine. The absence of specific pharmacology renders functional and structural studies of K2P channels difficult. The aim of this project is to study K2P TREK channel functions and subunit organization using existing and novel optogenetic tools.

Our Strategy

Probing ion channel and receptor function in their native context requires pharmacological agents or gene invalidation (KO mice). However, selective ligands are lacking for many neuronal signaling proteins, including K2P channels. To adress TREK K2P channel function, we have decided to give a new phramacology on these channels which is the light. We recently developed TREKlight, a TREK1 K2P channel which is regulated by light using a photoswitchable tethered ligands. To optically control native TREK without overexpression, we have developed two novel scheme for optical remote control of native proteins using a “photoswitchable conditional subunit” (PCS) and the StarTREK mouse model (the WT-TREK1 channel gene has been replaced by TREKlight). It is hard to predict with StarTREK or TREK1-PCS if the determined functions are carried by TREK1 alone or a TREK1 subunit combined with another K2P subunit.  To determine the TREK subunit combination, we developed the single-molecule pull-down (“SiMPull”) assay allowing direct visualization of antibody-immobilized individual protein complexes on polyethylene glycol-passivated coverslip.  We have already validated these approaches and used it to show that TREK1 can, heteromerize, identify TREK1 as a component of the hippocampal GABAB current described 30 years ago and demonstrate how a lipid (phosphatidic acid) can act specifically on a TREK target via an enzyme.

Research Aims

The absence of specific, commercially available pharmacology has made it difficult to measure the contribution of TREK1 current to leak currents in various cell types. By using primary cultured cells or slices from StarTREK mice or from TREK1-PCS infected mice, we are currently determining the cellular functions of TREK channels.

Role of TREK1 in basic neuronal functions. TREK1 closing induces a clear modification of the ac

Role of TREK1 in synaptic transmission and LTP or LTD induction. TREK‐1 is the mammalian homolog of the Aplysia S‐type channel (20), which is regulated by 5-HT and involved in simple forms of learning and memory (3).

Role in astrocytes. TREK1 has been identified to mediate the non-vesicular fast glutamate released from astrocytes. We will quantify and study the function of TREK1 current in astrocytes.

Several members of the TREK channel subfamily, and more generally the K2P channel family, show overlapping expression patterns in many brain regions which raises the question: do these channels heteromerize and what are the functions of these heteromers? We are determining potential TREK1 heteromer formation using a combination of SiMPull and PCS.

Postdocs

BUTENKO Olena

PreDocs

AVALOS PRADO Pablo
ROYAL Perrine

Engineers & Technicians

WDZIEKONSKI Brigitte

 

  1. Rayaprolu, V, Royal, P, Stengel, K, Sandoz, G, Kohout, SC. Dimerization of the voltage-sensing phosphatase controls its voltage-sensing and catalytic activity. J. Gen. Physiol. 2018;150 (5):683-696. doi: 10.1085/jgp.201812064. PubMed PMID:29695412 PubMed Central PMC5940254.
  2. Song, OR, Kim, HB, Jouny, S, Ricard, I, Vandeputte, A, Deboosere, N et al.. A Bacterial Toxin with Analgesic Properties: Hyperpolarization of DRG Neurons by Mycolactone. Toxins (Basel). 2017;9 (7):. doi: 10.3390/toxins9070227. PubMed PMID:28718822 PubMed Central PMC5535174.
  3. Levitz, J, Royal, P, Comoglio, Y, Wdziekonski, B, Schaub, S, Clemens, DM et al.. Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels. Proc. Natl. Acad. Sci. U.S.A. 2016;113 (15):4194-9. doi: 10.1073/pnas.1522459113. PubMed PMID:27035963 PubMed Central PMC4839437.
  4. Song, OR, Marion, E, Comoglio, Y, Babonneau, J, Guerineau, N, Sandoz, G et al.. [Mycolactone: the amazing analgesic mycobacterial toxin]. Med Sci (Paris). 2016;32 (2):156-8. doi: 10.1051/medsci/20163202007. PubMed PMID:26936171 .
  5. Harb, K, Magrinelli, E, Nicolas, CS, Lukianets, N, Frangeul, L, Pietri, M et al.. Area-specific development of distinct projection neuron subclasses is regulated by postnatal epigenetic modifications. Elife. 2016;5 :e09531. doi: 10.7554/eLife.09531. PubMed PMID:26814051 PubMed Central PMC4744182.
  6. Comoglio, Y, Levitz, J, Kienzler, MA, Lesage, F, Isacoff, EY, Sandoz, G et al.. Phospholipase D2 specifically regulates TREK potassium channels via direct interaction and local production of phosphatidic acid. Proc. Natl. Acad. Sci. U.S.A. 2014;111 (37):13547-52. doi: 10.1073/pnas.1407160111. PubMed PMID:25197053 PubMed Central PMC4169921.
  7. Marion, E, Song, OR, Christophe, T, Babonneau, J, Fenistein, D, Eyer, J et al.. Mycobacterial toxin induces analgesia in buruli ulcer by targeting the angiotensin pathways. Cell. 2014;157 (7):1565-76. doi: 10.1016/j.cell.2014.04.040. PubMed PMID:24949969 .
  8. Guyon, A, Kussrow, A, Olmsted, IR, Sandoz, G, Bornhop, DJ, Nahon, JL et al.. Baclofen and other GABAB receptor agents are allosteric modulators of the CXCL12 chemokine receptor CXCR4. J. Neurosci. 2013;33 (28):11643-54. doi: 10.1523/JNEUROSCI.6070-11.2013. PubMed PMID:23843532 PubMed Central PMC4299549.
  9. Sandoz, G, Levitz, J. Optogenetic techniques for the study of native potassium channels. Front Mol Neurosci. 2013;6 :6. doi: 10.3389/fnmol.2013.00006. PubMed PMID:23596388 PubMed Central PMC3622882.
  10. Sandoz, G, Isacoff, EY. [Optical remote control of native ion channels]. Med Sci (Paris). 2012;28 (11):934-7. doi: 10.1051/medsci/20122811011. PubMed PMID:23171896 .
  11. Sandoz, G, Levitz, J, Kramer, RH, Isacoff, EY. Optical control of endogenous proteins with a photoswitchable conditional subunit reveals a role for TREK1 in GABA(B) signaling. Neuron. 2012;74 (6):1005-14. doi: 10.1016/j.neuron.2012.04.026. PubMed PMID:22726831 PubMed Central PMC3383668.
  12. Noël, J, Sandoz, G, Lesage, F. Molecular regulations governing TREK and TRAAK channel functions. Channels (Austin). ;5 (5):402-9. doi: 10.4161/chan.5.5.16469. PubMed PMID:21829087 PubMed Central PMC3265763.
  13. Sandoz, G, Bell, SC, Isacoff, EY. Optical probing of a dynamic membrane interaction that regulates the TREK1 channel. Proc. Natl. Acad. Sci. U.S.A. 2011;108 (6):2605-10. doi: 10.1073/pnas.1015788108. PubMed PMID:21262820 PubMed Central PMC3038738.
  14. Feliciangeli, S, Tardy, MP, Sandoz, G, Chatelain, FC, Warth, R, Barhanin, J et al.. Potassium channel silencing by constitutive endocytosis and intracellular sequestration. J. Biol. Chem. 2010;285 (7):4798-805. doi: 10.1074/jbc.M109.078535. PubMed PMID:19959478 PubMed Central PMC2836085.
  15. 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 (34):14628-33. doi: 10.1073/pnas.0906267106. PubMed PMID:19667202 PubMed Central PMC2732798.
  16. Sandoz, G, Lesage, F. Protein complex analysis of native brain potassium channels by proteomics. Methods Mol. Biol. 2008;491 :113-23. doi: 10.1007/978-1-59745-526-8_9. PubMed PMID:18998088 .
  17. Sandoz, G, Tardy, MP, Thümmler, S, Feliciangeli, S, Lazdunski, M, Lesage, F et al.. Mtap2 is a constituent of the protein network that regulates twik-related K+ channel expression and trafficking. J. Neurosci. 2008;28 (34):8545-52. doi: 10.1523/JNEUROSCI.1962-08.2008. PubMed PMID:18716213 .
  18. Feliciangeli, S, Bendahhou, S, Sandoz, G, Gounon, P, Reichold, M, Warth, R et al.. Does sumoylation control K2P1/TWIK1 background K+ channels?. Cell. 2007;130 (3):563-9. doi: 10.1016/j.cell.2007.06.012. PubMed PMID:17693262 .
  19. Sandoz, G, Thümmler, S, Duprat, F, Feliciangeli, S, Vinh, J, Escoubas, P et al.. AKAP150, a switch to convert mechano-, pH- and arachidonic acid-sensitive TREK K(+) channels into open leak channels. EMBO J. 2006;25 (24):5864-72. doi: 10.1038/sj.emboj.7601437. PubMed PMID:17110924 PubMed Central PMC1698884.
  20. Sandoz, G, Lopez-Gonzalez, I, Stamboulian, S, Weiss, N, Arnoult, C, De Waard, M et al.. Repositioning of charged I-II loop amino acid residues within the electric field by beta subunit as a novel working hypothesis for the control of fast P/Q calcium channel inactivation. Eur. J. Neurosci. 2004;19 (7):1759-72. doi: 10.1111/j.1460-9568.2004.03216.x. PubMed PMID:15078550 .
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2016 - Travel Grant award for SFN - INSCOPIX

2012 - Laboratory of Excellence LABEX awarded

2012 - ATIP-AVENIR award

2009 - Fulbright award

2009 - Philippe Foundation awarded

2007 - Prix Jean-Louis Parrot - French Society for Promotion of Sciences (AFAS)

iBV - Institut de Biologie Valrose

"Sciences Naturelles"

Université Nice Sophia Antipolis
Faculté des Sciences
Parc Valrose
06108 Nice cedex 2