Molecular determinants of chemical modulation of two‐pore domain potassium channels

Șterbuleac, Daniel

doi:10.1111/cbdd.13571

Cited by 16 publications

(14 citation statements)

References 85 publications

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“…A range of physical and chemical signals control K2P function (Enyedi and Czirjak, 2010;Feliciangeli et al, 2014;Renigunta et al, 2015) and various K2P subtypes have emerging roles in a multitude of physiological responses and pathological conditions such as action potential propagation in myelinated axons (Brohawn et al, 2019;Kanda et al, 2019), anesthetic responses (Heurteaux et al, 2004;Lazarenko et al, 2010), microglial surveillance (Madry et al, 2018), sleep duration (Yoshida et al, 2018), pain (Alloui et al, 2006;Devilliers et al, 2013;Vivier et al, 2017), arrythmia (Decher et al, 2017), ischemia (Heurteaux et al, 2004;Laigle et al, 2012;Wu et al, 2013), cardiac fibrosis (Abraham et al, 2018), depression (Heurteaux et al, 2006), migraine (Royal et al, 2019), intraocular pressure regulation (Yarishkin et al, 2018), and pulmonary hypertension (Lambert et al, 2018). Although there have been recent advances in identifying new K2P modulators (Bagriantsev et al, 2013;Lolicato et al, 2017;Pope et al, 2018;Su et al, 2016;Tian et al, 2019;Vivier et al, 2017;Wright et al, 2019) and in defining key structural aspects of K2P channel pharmacology (Dong et al, 2015;Lolicato et al, 2017;Schewe et al, 2019), as is the case with many ion channel classes, pharmacological agents targeting K2Ps remain poorly developed and limit the ability to probe K2P mechanism and biological functions (Sterbuleac, 2019).…”

Section: Introductionmentioning

confidence: 99%

Polynuclear Ruthenium Amines Inhibit K2P Channels via a “Finger in the Dam” Mechanism

Pope

Lolicato

Minor

2020

Cell Chemical Biology

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The trinuclear ruthenium amine Ruthenium Red (RuR) inhibits diverse ion channels including K2P potassium channels, TRPs, the mitochondrial calcium uniporter, CALHMs, ryanodine receptors, and Piezos. Despite this extraordinary array, there is very limited information for how RuR engages its targets. Here, using X-ray crystallographic and electrophysiological studies of an RuR-sensitive K2P, K2P2.1 (TREK-1) I110D, we show that RuR acts by binding an acidic residue pair comprising the 'Keystone inhibitor site' under the K2P CAP domain archway above the channel pore. We further establish that Ru360, a dinuclear ruthenium amine not known to affect K2Ps, inhibits RuR-sensitive K2Ps using the same mechanism. Structural knowledge enabled a generalizable RuR 'super-responder' design strategy for creating K2Ps having nanomolar sensitivity. Together, the data define a 'finger in the dam' inhibition mechanism acting at a novel K2P inhibitor binding site. These findings highlight the polysite nature of K2P pharmacology and provide a new framework for K2P inhibitor development..

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Section: Introductionmentioning

confidence: 99%

Polynuclear Ruthenium Amines Inhibit K2P Channels via a “Finger in the Dam” Mechanism

Pope

Lolicato

Minor

2020

Cell Chemical Biology

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“…GI‐530159 was shown to be active on a TREK1 clone lacking the N‐terminus (Loucif et al, 2018). ML67‐33 action requires the C‐type gate near the selectivity filter of the channel (Bagriantsev et al, 2013) and a cryptic binding site for ML335 and ML402 has been identified behind the selectivity filter at the interface between P1 and M4 segments, which allow these compounds to activate the C‐type gate (Lolicato et al, 2017; Şterbuleac, 2019). BL‐1249 also stimulates the C‐type gate but binds to a different site.…”

Section: Discussionmentioning

confidence: 99%

TREK1 channel activation as a new analgesic strategy devoid of opioid adverse effects

Busserolles

Soussia

Pouchol

et al. 2020

British J Pharmacology

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Background and Purpose Opioids are effective painkillers. However, their risk–benefit ratio is dampened by numerous adverse effects and opioid misuse has led to a public health crisis. Safer alternatives are required, but isolating the antinociceptive effect of opioids from their adverse effects is a pharmacological challenge because activation of the μ opioid receptor triggers both the antinociceptive and adverse effects of opioids. Experimental Approach The TREK1 potassium channel is activated downstream of μ receptor and involved in the antinociceptive activity of morphine but not in its adverse effects. Bypassing the μ opioid receptor to directly activate TREK1 could therefore be a safer analgesic strategy. Key Results We developed a selective TREK1 activator, RNE28, with antinociceptive activity in naive rodents and in models of inflammatory and neuropathic pain. This activity was lost in TREK1 knockout mice or wild‐type mice treated with the TREK1 blocker spadin, showing that TREK1 is required for the antinociceptive activity of RNE28. RNE28 did not induce respiratory depression, constipation, rewarding effects, or sedation at the analgesic doses tested. Conclusion and Implications This proof‐of‐concept study shows that TREK1 activators could constitute a novel class of painkillers, inspired by the mechanism of action of opioids but devoid of their adverse effects.

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“…developed a virtual screening but in the extracellular cap of K 2P channels to identify inhibitors targeting this site [38]. Nevertheless, due to their pharmacological potential as protein targets in diverse diseases, much evidence has been recently accumulated regarding the molecular characteristics underlying the interactions between different compounds and K 2P channels [39].…”

Section: Discussionmentioning

confidence: 99%

Discovery of Novel TASK-3 Channel Blockers Using a Pharmacophore-Based Virtual Screening

Ramírez

Concha

Arévalo

et al. 2019

IJMS

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TASK-3 is a two-pore domain potassium (K2P) channel highly expressed in the hippocampus, cerebellum, and cortex. TASK-3 has been identified as an oncogenic potassium channel and it is overexpressed in different cancer types. For this reason, the development of new TASK-3 blockers could influence the pharmacological treatment of cancer and several neurological conditions. In the present work, we searched for novel TASK-3 blockers by using a virtual screening protocol that includes pharmacophore modeling, molecular docking, and free energy calculations. With this protocol, 19 potential TASK-3 blockers were identified. These molecules were tested in TASK-3 using patch clamp, and one blocker (DR16) was identified with an IC50 = 56.8 ± 3.9 μM. Using DR16 as a scaffold, we designed DR16.1, a novel TASK-3 inhibitor, with an IC50 = 14.2 ± 3.4 μM. Our finding takes on greater relevance considering that not many inhibitory TASK-3 modulators have been reported in the scientific literature until today. These two novel TASK-3 channel inhibitors (DR16 and DR16.1) are the first compounds found using a pharmacophore-based virtual screening and rational drug design protocol.

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Molecular determinants of chemical modulation of two‐pore domain potassium channels

Cited by 16 publications

References 85 publications

Polynuclear Ruthenium Amines Inhibit K2P Channels via a “Finger in the Dam” Mechanism

Polynuclear Ruthenium Amines Inhibit K2P Channels via a “Finger in the Dam” Mechanism

TREK1 channel activation as a new analgesic strategy devoid of opioid adverse effects

Discovery of Novel TASK-3 Channel Blockers Using a Pharmacophore-Based Virtual Screening

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