2025/08/25 by Edward Mendez-Otalvaro, Mendez-Otalvaro, Edward, Wojciech Kopeć +5 · 1 voice
Biochemistry, Genetics and Molecular Biology · Neuroscience · #Ion channel regulation and function #Ion Channels and Receptors #Nicotinic Acetylcholine Receptors Study
paper · pdf · doi:10.1080/19336950.2025.2602975
openalex created_date 2025/12/23 · openalex publication_date 2025/12/23 · openalex updated_date 2026/07/02
2.1) K2P channel. This pocket, located close to the selectivity filter, accommodates agonists that enhance the channel's activity. Since its discovery, equivalent sites in other K2P channels have been shown to bind various ligands, both endogenous and exogenous. In this review, we attempt to elucidate how the modulator pocket contributes to K2P channel activation. To this end, we first describe the gating mechanisms reported in the literature and rationalize their modes of action. We then highlight previous experimental and computational evidence for agonists that bind to the modulator pocket, together with mutations at this site that affect gating. Finally, we elaborate how the activation signal arising from the modulator pocket is transduced to the gates in K2P channels. In doing so, we outline a potential common modulator pocket architecture across K2P channels: a largely amphipathic structure - consistent with the expected properties of a pocket exposed at the interface between a hydrophobic membrane and the aqueous solvent - but still with some important channel-sequence-variations. This architecture and its key differences can be leveraged for the design of new selective and potent modulators.