Guillaume Sandoz, institut de Biologie Valrose - Nice

Le 15 March 2024

Amphi DE

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11h30

Optical Probing of TREK Potassium Channel fonctions in Pain and Migraine induction

Optical Probing of TREK Potassium Channel fonctions in Pain and Migraine induction

Guillaume Sandoz, PhD, DR1 CNRS
Principal Investigateur
institut de Biologie Valrose, Nice

Abstract

Migraine and chronic pain are prevalent neurological disorders, affecting 15% and 25% of the global population respectively. These conditions are linked to the electrical hyperexcitability of trigeminal and DRG neurons, with their activity modulated by two-pore-domain potassium channels (K2P). Our recent findings underscore the pivotal role of these channels in modulating nociceptor excitability, thus influencing pain and migraine onset. We have leveraged this knowledge to develop methods for the remote, light-guided control of pain in vivo, offering precise spatiotemporal resolution. The first segment of this presentation will explore how certain genetic mutations in TRESK enhance neuronal excitability and trigger migraines, while others do not. We introduce the concept of frameshift mutation-induced alternative translation initiation (fsATI). This intricate mechanism produces both the expected C-terminal truncated protein and an additional fragment lacking the N-terminal domain. This fragment, by interfering with TREK1 and TREK2 channels, amplifies trigeminal sensory neuron excitability and induces migraines. Our findings not only clarify the molecular underpinnings of migraine but also establish TREK1 and TREK2 as effective targets, whose activation can significantly reduce migraine onset. The latter part will delve into the development of LAKI (Light Activated K+ channel Inhibitor), an innovative tool enabling precise, light-based control of neuronal activity. LAKI specifically targets pain-associated TREK and TRESK channels. With defined light wavelengths, LAKI can reversibly modulate these channels, thus offering immediate and non-invasive control over pain and nociception in animal models, bypassing the need for genetic or viral interventions. Together, these studies not only highlight the crucial function of K2P channels in managing neuronal excitability and pain perception but also offer pioneering insights and tools for manipulating these channels. The examination of fsATI alongside the introduction of LAKI enriches our understanding of neurological disorders and pave the way for innovative therapies and research methodologies in the management of pain and migraines.

Biography

I am currently Research Director at the French National Centre for Scientific Research (CNRS) and serve as the Principal Investigator of the Biology of Ion Channels (BIC) lab at the Institute of Biology Valrose (iBV) in Nice, France. My career began with a PhD in Neuroscience from Aix-Marseille University, under the mentorship of Michael Dewaard. Subsequently, I joined the Lazdunski and Lesage Labs in Valbonne, transitioning from a postdoctoral researcher to a CNRS researcher with a permanent position as “Chargé de Recherche”. During this period, I conducted seminal work on the regulation of leak potassium currents by Two-Pore-Domain channels K2P, contributing significantly to the field with publications in EmboJ, J. NSci, and Cell.
In 2009, my academic pursuits led me to UC Berkeley as a Fulbright Visiting Scholar in the Isacoff Lab. There, I was part of a pioneering team that discovered a novel family of ion channels, providing insights into the evolutionary trajectory of Glutamate receptors (Janovjak*, Sandoz* and Isacoff, Nature Com, 2011), and delved into various facets of K2P pharmacology (Sandoz et al., PNAS 2011), including the elucidation of the molecular mechanisms of K2P channel activation by GABAB receptors Sandoz et al., Neuron 2012).
Returning to France in 2012, I obtained the ATIP AVENIR grant and established my own lab at the iBV in 2013. My team is dedicated to understanding neuroexcitability in both typical and pathological conditions. We have made breakthrough discoveries concerning protein complexes and their configurations (Comoglio et al. 2014 PNAS, Levitz et al., PNAS 2016, Avalos Prado et al., Cell 2021), delineated the molecular mechanisms of migraine inheritance (Royal et al., Neuron 2019; Avalos Prado et al., iScience 2021), and developed innovative optogenetic tools to remote control, in freely moving animals, pain (Landra et al., 2023 Nature Com) and muscle contraction (Neira-Oliveira et al., Nature Com 2024). Our lab's work extends beyond the theoretical, with significant clinical implications in treating conditions such as dry eye syndromes and cystic fibrosis, and industrial applications.

Mis à jour le 01 February 2024.