Speakers: Delphine Bichet & Franck Chatelain, Institut de Pharmacologie Moléculaire et Cellulaire, Nice-Sophia Antipolis, France
Titles: Two pore domain THIK potassium channels regulate acute and chronic pain signaling/Two pore domain TWIK1 channel, a potassium channel whose pH sensitivity alters its ionic selectivity
This will be a joint seminar (1 hour total), please see both abstracts below.
External attendees, if you would like to attend in person please contact Max Behzadi: mbehzadi@mrclmb.ac.uk
Delphine’s Abstract: Two-pore domain potassium channels regulate neuronal excitability through hyperpolarizing leak currents and play important roles in sensory physiology. Among them, THIK1 and THIK2 remain poorly characterized despite their strong enrichment in nociceptive dorsal root ganglion (DRG) neurons. In this seminar, we will present a multidisciplinary study combining molecular analyses, electrophysiology, and behavioral approaches to investigate the contribution of THIK channels to sensory neuron excitability and pain processing under physiological and inflammatory conditions. THIK1 and THIK2 expression patterns were characterized in mouse DRG, while whole-cell recordings and behavioral analyses were used to explore the consequences of THIK deletion on neuronal function and nociceptive responses. Our findings reveal an unexpected role for THIK channels in the regulation of sensory neuron activity and thermal pain sensitivity, highlighting these poorly understood K2P channels as potential new players in inflammatory pain mechanisms and possible therapeutic targets for chronic pain disorders.
Franck’s Abstract: Despite being the first channel in the K2P family to be cloned, TWIK1 remains largely mysterious in terms of its physiological role. We have shown that its sensitivity to extracellular pH is accompanied by a change in its ionic selectivity, thereby reinforcing questions about its function. At neutral physiological pH, TWIK1 is, like most potassium channels, selective for K+ ions. However, when exposed to a pH below 6—as occurs in the recycling endosomes it transits during intracellular trafficking—the channel undergoes conformational changes. These changes alter the structure of its selectivity filter, rendering TWIK1 permeable to Na+ ions. We have identified the molecular determinants responsible for this pH sensitivity and proposed a model describing the sequence of molecular events occurring around the selectivity filter during the gradual acidification of the extracellular environment. Research into the physiological role of this dynamic selectivity suggests that, in certain functional contexts, TWIK1’s preference for potassium ions may not be absolute, nor even indispensable.
