Gildas Loussouarn, Isabelle Baro, Michel de Waard

 

Using therapeutic peptides to correct dysfunction in voltage-gated channels

In our previous works, we have shown, in heterologous expression systems, that intracellular peptides mimicking regions of voltage-gated potassium (Kv7.1, Kv11.1, Kv10.2) and sodium (Nav1.4) channels can modulate the activity of these channels. The next goal is to test a potential therapeutic application. To this end, we will use human cardiomyocytes derived from induced pluripotent stem cells to test whether Kv11.1-specific activating peptides can be used to correct dysfunctions in Kv11.1 (hERG) channels, due to mutations identified in patients presenting with type 2 Long QT syndrome.

In parallel, we will use the Cryo-elecron microscopy to generate structures of peptides-bound Kv11.1, through collaborations with Olga Sokolova (Lomonosov University, Moscow) and Philippe Moreau (Institut des Matériaux de Nantes). Using these structures, we will modify the peptides to increase their affinity to the channel and test them in patch-clamp.



Publications


Editorial: Molecular Mechanisms of Voltage-Gating in Ion Channels. Loussouarn G, Tarek M. Front Pharmacol. 2021, 12:768153. doi: 10.3389/fphar.2021.768153. eCollection 2021.

Up-regulation of voltage-gated sodium channels by peptides mimicking S4-S5 linkers reveals a variation of the ligand-receptor mechanism. Malak OA, Abderemane-Ali F, Wei Y, Coyan FC, Pontus G, Shaya D, Marionneau C, Loussouarn G. Sci Rep. 2020, 10:5852. doi: 10.1038/s41598-020-62615-6.

Detergent-free solubilization of human Kv channels expressed in mammalian cells. Karlova MG, Voskoboynikova N, Gluhov GS, Abramochkin D, Malak OA, Mulkidzhanyan A, Loussouarn G, Steinhoff H-J, Shaitan KV, Sokolova OS. Chem Phys Lipids 2019;219:50–57.

Voltage-dependent activation in EAG channels follows a ligand-receptor rather than a mechanical-lever mechanism. Malak OA, Gluhov GS, Grizel AV, Kudryashova KS, Sokolova OS, Loussouarn G. J Biol Chem 2019;294:6506–6521.

hERG S4-S5 linker acts as a voltage-dependent ligand that binds to the activation gate and locks it in a closed state. Malak OA, Es-Salah-Lamoureux* Z, Loussouarn* G. Sci Rep 2017;7:113.

Funding