Molecular Pharmacology of K Potassium Channels

Cellular Physiology Cell Physiol Biochem 2021;55(S3):87-107 DOI: 10.33594/00000033910.33594/000000339 © 2021 The Author(s).© 2021 Published The Author(s) by and Biochemistry Published online: online: 6 6March March 2021 2021 Cell Physiol BiochemPublished Press GmbH&Co. by Cell Physiol KG Biochem 87 Press GmbH&Co. KG, Duesseldorf Decher et al.: Molecular Pharmacology of K Channels Accepted: 12 January 2021 2P www.cellphysiolbiochem.com This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 Interna- tional License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission. Review Molecular Pharmacology of K2P Potassium Channels Niels Dechera Susanne Rinnéa Mauricio Bedoyab,c Wendy Gonzalezb,c Aytug K. Kipera aVegetative Physiology, Institute for Physiology and Pathophysiology, Philipps-University Marburg, Marburg, Germany, bCentro de Bioinformática y Simulación Molecular, Universidad de Talca, Talca, Chile, cMillennium Nucleus of Ion Channels-Associated Diseases (MiNICAD), Universidad de Talca, Talca, Chile Key Words Drug binding sites • K2P potassium channels • Ion channels • Molecular pharmacology Abstract Potassium channels of the tandem of two-pore-domain (K2P) family were among the last potassium channels cloned. However, recent progress in understanding their physiological relevance and molecular pharmacology revealed their therapeutic potential and thus these channels evolved as major drug targets against a large variety of diseases. However, after the initial cloning of the fifteen family members there was a lack of potent and/or selective modulators. By now a large variety of K2P channel modulators (activators and blockers) have been described, especially for TASK-1, TASK-3, TREK-1, TREK2, TRAAK and TRESK channels. Recently obtained crystal structures of K2P channels, alanine scanning approaches to map drug binding sites, in silico experiments with molecular dynamics simulations (MDs) combined with electrophysiological studies to reveal the mechanism of channel inhibition/activation, yielded a good understanding of the molecular pharmacology of these channels. Besides summarizing drugs that were identified to modulate 2PK channels, the main focus of this article is on describing the differential binding sites and mechanisms of channel modulation that are utilized by the different 2PK channel blockers and activators. © 2021 The Author(s). Published by Cell Physiol Biochem Press GmbH&Co. KG Introduction Tandem of two-pore-domain potassium (K2P) channels belong to the latest family of potassium channels cloned, with TOK1 from Saccharomyces cerevisiae discovered in 1995 [1]. The mammalian K2P potassium channel family contains 15 members with different subfamilies, characterized by mechanistic hallmarks like acid as inhibition, the first channel stretch activation, alkaline activation and halothane inhibition (shown in Fig. 1a). K2P channels have N. Decher and S. Rinné contributed equally to this work. Prof. Dr. Niels Decher Vegetative Physiology Institute for Physiology and Pathophysiology, Philipps-University Marburg Deutschhausstraße 1-2, 35037 Marburg (Germany) Tel. +49 6421-28-62148, E-Mail [email protected] Cellular Physiology Cell Physiol Biochem 2021;55(S3):87-107 DOI: 10.33594/000000339 © 2021 The Author(s). Published by and Biochemistry Published online: 6 March 2021 Cell Physiol Biochem Press GmbH&Co. KG 88 Decher et al.: Molecular Pharmacology of K2P Channels four transmembrane domains and contain two pore loops and thus assemble as dimer in channel families (shown in Fig. 1b, 1c). The channels have a large extracellular M1-P1 loop order that four pore loops form the potassium selectivity filter, similar as in other potassium which has been identified in early studies as self-interacting domain (‘SID’)2P and channels is relevant (shown for the dimerization of the channels (shown in Fig. 1b) [2]. In fact, the extracellular M1-P1 loop toxinsforms thefrom so binding called ‘cap’ to the structure pore region which [4]. is aHowever, structural whether hallmark there of the are K other physiological functionsin Fig. 1b, that 1c) can [3-9]. be assignedIt has been to this postulated unique structure that the hasextracellular not been addressed‘cap’ prevents yet. Although classical K2P appeared to solely obey the Goldman-Hodgkin-Katz equation for a potassium selective hole, we knowchannels in the were meantime initially that described these channels as leak arechannels highly withregulated an outward by a plethora rectification of different that stimuli (shown in Fig. 1a). Moreover, these channels are in fact voltage sensitive with potassium acting as the actual voltage sensor, meaning similar to the CLC chloride channel family [10], the permeating ion actually also gates the channel [11]. Thus, K2P channels are of the channel at depolarized potentials. potassium gated2P channelspotassium were channels described with toa potassium have a unique efflux pharmacology increasing the compared open probability to other potassium channel families, as they were less sensitive to the classical potassium channel + 2+ blockersInitially, like KTEA, 4-AP, Cs or Ba . Channels of the K2P family appeared to be drug resistant. However, classical open channel blockers of ion channels share a conserved binding site scheme with about two or more interacting residues of the pore forming helices and an additional binding to residues of the pore signature sequence (shown in Fig. 1d). This binding Fig. 1. The K2P 2P channels with their physiological or pharmacological + K+ channel family. (a) Dendrogram of K + key+ modulators. TWIK: Tandem of P-domains in a weak+ inward rectifying K channel, TREK: TWIK-related+ K channel, TRAAK: TWIK-related arachidonic+ acid activated K channel, TASK: TWIK-related acid-sensitive channel. (b) Membrane topology of K2P channels depicting transmembrane channel, TALK: domains TWIK-related in blue, alkaline the pore activated helices in K red channel, and the THIK: extracellular TWIK-related cap structurehalothane in inhibited purple. (c)K channel, TRESK: TWIK-related spinal cord K 2P are illustrated in blue, the pore helices in red and the extracellular cap ‘ ’ ofIllustration the conserved of the scheme crystal structureof drug binding of the Ksites channel in voltage TWIK-1 gated (PDB ion channels.ID: 3UKM). The Transmembrane typical binding domains sites of ‘ ’ structure in purple. (d) Illustration formula of quaternary ammonium compounds, which are classical pore blockers with different alkyl side chainclassical lengths. pore blockers are indicated with purple stars. CC: central cavity; SF: selectivity filter (e) Chemical Cellular Physiology Cell Physiol Biochem 2021;55(S3):87-107 DOI: 10.33594/000000339 © 2021 The Author(s). Published by and Biochemistry Published online: 6 March 2021 Cell Physiol Biochem Press GmbH&Co. KG 89 Decher et al.: Molecular Pharmacology of K2P Channels site pattern can be found in different potassium channel families, but also in voltage-gated sodium and calcium channels [12-20]. Thus, it appears unlikely that K2P channels in general 2P channels are also highly sensitive to classical pore block by quaternary ammonium compounds (QA) (shownshould be in resistantFig. 1e), however, to classical presumably pore blockers. due to In differences the meantime, in the we architecture know that of K the central alkyl side chains, like TPenA or THexA (shown in Fig. 1e), to be stabilized underneath the cavity providing more lateral space underneath the selectivity filter, the QAs need longer selectivity filter by interact with the pore forming helices [21]. While the sensitivity of TASK-3 channels to extracellular polyamines and ruthenium red (RR) has 2Pbeen channels described and very early after cloning of the TASK channels [22-29],2P there was for a longer time a lack of potent small compound inhibitors. A decade after cloning of the first K functionalTASK-1 [23, studies 30, 31], of we the described channel inthe native first potenttissue [33],K channel leading blocker for instance A293 to[32]. the Strikingly, isolation the development of a potent and selective TASK-1 channel blocker opened the door for2P channels there are still no highly potent and selective blockers or activators available (shown inof Tablea whole 1-8). cell Thus, TASK-1 we eagerlycurrent anticipatein ventricular the developmentmyocytes [32]. of However,small compound for most modulators of the K for all K2P channels as this will, besides the generation and study of transgenic mouse models, 2P channels in different organs. definitely foster our research aiming to understand the physiological role of K and TALK channels, there are in the meantime many potent activators and blockers described However, while we still have a poor understanding of the pharmacology of TWIK, THIK separate sections, especially by focusing on the mechanistic models of channel modulation andfor the the channelsdifferential of bindingthe TASK sites and utilized TREK-subfamily, by the drugs. which we would like to summarize in Table 1. 2P channel subfamilies List of inhibitors of the TWIK, THIK and TALK K ͷͲ ȋρȌ Ǧͳ ≈95 Ǥǡͳͻͻ͸ ͺ͸Ͳͷͺ͸ͻ Ǥǡͳͻͻͻ ͳͲʹͲͳ͸ͺʹ ≈50 Ǥǡͳͻͻ͸ ͺ͸Ͳͷͺ͸ͻ Ǧʹ ǤǡʹͲͲͲ ͳͲͺͺ͹ͳͺ͹ ǤǡʹͲͲͲ ͳͲͺͺ͹ͳͺ͹ ǦǦͳ ǤǡʹͲͳ͸ ʹ͹Ͳͻͳͻͻ͹ ǤǡʹͲͲͺ ͳͺͷͳ͸Ͳ͸ͻ ǤǡʹͲͲͲ ͳͲͺͺ͹ͳͺ͹ ǤǡʹͲͲͲ ͳͲͺͺ͹ͳͺ͹ Ǧͳ ͳͺͻͻ ≈2 ǤǡʹͲͳͳ ʹͳ͵͸ʹ͸ͳͻ ǤǡʹͲͲͺ ͳͺͷͳ͸Ͳ͸ͻ

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