Events

Date: 8 September 2026   Time: 15:00 - 16:00

Title: Rethinking how we target ion channels in epilepsy: structural pharmacology and protein coupling axes.

Abstract: Ion channel drug discovery often fails due to the challenge of selectively blocking highly conserved ion channel pores, leading to off-target toxicity and inconsistent clinical efficacy. Recognition is growing that overcoming these barriers requires alternative therapeutic strategies such as exploiting distinct gating states and auxiliary regulatory mechanisms. To illustrate this approach, I will first highlight my recent work elucidating the mechanisms of subtype-selective modulation of HCN1. By integrating electrophysiology and structural pharmacology, we resolved how state-dependent modulation can phenotypically rescue epilepsy-causing mutations at the molecular level.

Translating this into my future research vision, I will focus on defining how regulatory mechanisms outside of the ion channel pore, specifically local ionic microenvironments and regulatory interactions, contribute to and shape aberrant channel gating. Using the NALCN sodium leak channelosome and the epilepsy-associated KCNT1 potassium channel as a model regulatory axis, I will outline my strategy to characterise and later therapeutically exploit these microdomains. Ultimately, this approach aims to translate basic discoveries into new therapeutic strategies for Developmental and Epileptic Encephalopathies (DEEs) and other rare neurological diseases.