SANDOZ

Guillaume SANDOZ

Biology of ion channels

Main interests

  • Regulation of neuroexcitability
  • Structure-function studies of ion channels
  • Subunit organization of ion channels
  • Channelopathy

Scientific Questions

Maintenance of a negative resting membrane potential underlies the basis of neuronal excitability. This negative potential is generated by a potassium leak current mediated by Two-Pore-Domain Potassium (K2P) channels. K2P channels are notably involved in mood regulation and migraine. To address their role, we developed a TREK1 channel that is controlled by light, both in-vitro (TREKlight) and in-vivo (StarTREK mouse model). Using these tools in combination with single molecule fluorescence pull down assays (SiMPull)—our project aims to address K2P channel’s physiological (neuroexcitability, plasticity…) and pathological (such as depression and migraine) functions and to determine which channels subtypes are, along with finding new drug  targets, involved in these aforementioned processes.

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 engeeniered 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using a “photoswitchable conditional subunit” (PCS) and the StarTREK mouse model (the WT-TREK1 channel gene has been replaced by TREKlight).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 contibutes to the hippocampal GABAB current described 30 years ago, demonstrate how a lipid (phosphatidic acid) can act specifically on a TREK target via an enzyme and determine the channel function in Migraine inudction.

Research Aims

We recently demonstrated that migraine-associated frameshift mutations of TRESK, a two-pore-domain K+ channel, lead to the production of tow second protein fragments instead of one.The second fragment carries the pathophysiological function by inhibiting TREK1 and 2, and its production is due to a mechanism that we called frameshift mutation-induced Alternative Translation Initiation (fsATI). We aim now to determine if TREK agonists can be used to treat migraine.

To adress K2P channel functions such as excitability, adaptation, action potential duration, synaptic transmission and plasticity, we are using fresh brain slices in which we remote control the channel activity with light.

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 K2P heteromer formation and function using a combination of SiMPull and PCS

Postdocs

EL HASSAR Lynda - +33
HAFNER Stéphanie - +33

PreDocs

AVALOS PRADO Pablo - +33 489150815
LANDRA WILLM Arnaud - +33

Engineers & Technicians

WDZIEKONSKI Brigitte - +33 489150815

 

  1. Royal, P, Sandoz, G. [Ion channels and mechanisms of inherited disease transmission causing migraine]. Med Sci (Paris). ;35 (8-9):608-610. doi: 10.1051/medsci/2019121. PubMed PMID:31539490 .
  2. Royal, P, Ávalos Prado, P, Wdziekonski, B, Sandoz, G. [Two-pore-domain potassium channels and molecular mechanisms underlying migraine]. Biol Aujourdhui. 2019;213 (1-2):51-57. doi: 10.1051/jbio/2019020. PubMed PMID:31274103 .
  3. Royal, P, Andres-Bilbe, A, Ávalos Prado, P, Verkest, C, Wdziekonski, B, Schaub, S et al.. Migraine-Associated TRESK Mutations Increase Neuronal Excitability through Alternative Translation Initiation and Inhibition of TREK. Neuron. 2019;101 (2):232-245.e6. doi: 10.1016/j.neuron.2018.11.039. PubMed PMID:30573346 .
  4. 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.
  5. 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.
  6. 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.
  7. 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 .
  8. 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.
  9. 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.
  10. 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 .
  11. 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.
  12. 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.
  13. 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 .
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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 .
  20. 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 PubMed Central PMC6671063.
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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)

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iBV - Institut de Biologie Valrose

"Sciences Naturelles"

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