Activation of TREK Currents by the Neuroprotective Agent Riluzole in Mouse Sympathetic Neurons

Cadaveira-Mosquera, Alba; Ribeiro, Sandro J.; Reboreda, Antonio; Pérez, Montse; Lamas, José Antonio

doi:10.1523/jneurosci.2791-10.2011

Cited by 41 publications

(64 citation statements)

References 67 publications

(91 reference statements)

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“…For comparison, a 10°C decrease in the bath solution was effective in only 20 seconds. TREK/TRAAK channels are also activated by the anticonvulsant and neuroprotective agent riluzole [70], [71]. As shown in figure 8B, application of 100 µM riluzole produced a full inhibition of cold-evoked responses (n = 2), consistent with the activation of TREK/TRAAK channels.…”

Section: Resultsmentioning

confidence: 71%

“…It must be stated that none of the drugs we used targets K 2p channels specifically. The lack of specific blockers for most K 2P channels is well known in the field [26], [79] and acknowledged in other recent publications characterizing native K 2P channels [71]. However, the effects of the different agonists and/or antagonists we used, drugs with different structural profiles, strongly converge on K 2P channels, as evidenced by the exclusive identification of K 2P -related publications when using simple search strategies in Pubmed that combine these terms (e.g.…”

Section: Discussionmentioning

confidence: 90%

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The Influence of Cold Temperature on Cellular Excitability of Hippocampal Networks

et al. 2012

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The hippocampus plays an important role in short term memory, learning and spatial navigation. A characteristic feature of the hippocampal region is its expression of different electrical population rhythms and activities during different brain states. Physiological fluctuations in brain temperature affect the activity patterns in hippocampus, but the underlying cellular mechanisms are poorly understood. In this work, we investigated the thermal modulation of hippocampal activity at the cellular network level. Primary cell cultures of mouse E17 hippocampus displayed robust network activation upon light cooling of the extracellular solution from baseline physiological temperatures. The activity generated was dependent on action potential firing and excitatory glutamatergic synaptic transmission. Involvement of thermosensitive channels from the transient receptor potential (TRP) family in network activation by temperature changes was ruled out, whereas pharmacological and immunochemical experiments strongly pointed towards the involvement of temperature-sensitive two-pore-domain potassium channels (K2P), TREK/TRAAK family. In hippocampal slices we could show an increase in evoked and spontaneous synaptic activity produced by mild cooling in the physiological range that was prevented by chloroform, a K2P channel opener. We propose that cold-induced closure of background TREK/TRAAK family channels increases the excitability of some hippocampal neurons, acting as a temperature-sensitive gate of network activation. Our findings in the hippocampus open the possibility that small temperature variations in the brain in vivo, associated with metabolism or blood flow oscillations, act as a switch mechanism of neuronal activity and determination of firing patterns through regulation of thermosensitive background potassium channel activity.

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Section: Resultsmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 90%

The Influence of Cold Temperature on Cellular Excitability of Hippocampal Networks

et al. 2012

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“…4 Many are drugs having numerous molecular targets or metabolites involved in multiple pathways such as local 46,47 and general 9,10,17 anesthetics, antidepressants, 9,19 neuroprotectants, 18,48 phospholipids, 38,49 protons, 36,39,50 and heavy metal ions. 17 Most of these K 2P 2.1 (TREK-1) modulators act at >100 μM, have limited effects on current amplitude, 4 and current enhancements of <2-fold.…”

Section: Discussionmentioning

confidence: 99%

A High-Throughput Functional Screen Identifies Small Molecule Regulators of Temperature- and Mechano-Sensitive K_2P Channels

Bagriantsev¹,

Ang²,

Gallardo-Godoy³

et al. 2013

ACS Chem. Biol.

109

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K2P (KCNK) potassium channels generate “leak” potassium currents that strongly influence cellular excitability and contribute to pain, somatosensation, anesthesia, and mood. Despite their physiological importance, K2Ps lack specific pharmacology. Addressing this issue has been complicated by the challenges that the leak nature of K2P currents poses for electrophysiology-based high-throughput screening strategies. Here, we present a yeast-based high-throughput screening assay that avoids this problem. Using a simple growth-based functional readout, we screened a library of 106,281 small molecules and identified two new inhibitors and three new activators of the mammalian K2P channel K2P2.1 (KCNK2, TREK-1). By combining biophysical, structure–activity, and mechanistic analysis, we developed a dihydroacridine analogue, ML67-33, that acts as a low micromolar, selective activator of temperature- and mechano-sensitive K2P channels. Biophysical studies show that ML67-33 reversibly increases channel currents by activating the extracellular selectivity filter-based C-type gate that forms the core gating apparatus on which a variety of diverse modulatory inputs converge. The new K2P modulators presented here, together with the yeast-based assay, should enable both mechanistic and physiological studies of K2P activity and facilitate the discovery and development of other K2P small molecule modulators.

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“…16,17 Potassium serves to stabilize the resting membrane potential, thereby modulating cell excitability in the central and peripheral nervous system. 8 Riluzole has shown effectiveness for the treatment of patients with amyotrophic lateral sclerosis at a recommended dose of 50 mg every 12 hours.…”

Section: Riluzolementioning

confidence: 99%

Translational potential of preclinical trials of neuroprotection through pharmacotherapy for spinal cord injury

Tator

Hashimoto

Raich

et al. 2012

SPI

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There is a need to enhance the pipeline of discovery and evaluation of neuroprotective pharmacological agents for patients with spinal cord injury (SCI). Although much effort and money has been expended on discovering effective agents for acute and subacute SCI, no agents that produce major benefit have been proven to date. The deficiencies of all aspects of the pipeline, including the basic science input and the clinical testing output, require examination to determine remedial strategies. Where has the neuroprotective/pharmacotherapy preclinical process failed and what needs to be done to achieve success? These are the questions raised in the present review, which has 2 objectives: 1) identification of articles that address issues related to the translational readiness of preclinical SCI pharmacological therapies; and 2) examination of the preclinical studies of 5 selected agents evaluated in animal models of SCI (including blunt force trauma, penetrating trauma, or ischemia). The 5 agents were riluzole, glyburide, magnesium sulfate, nimodipine, and minocycline, and these were selected because of their promise of translational readiness as determined by the North American Clinical Trials Network Consortium. The authors found that there are major deficiencies in the effort that has been extended to coordinate and conduct preclinical neuroprotection/pharmacotherapy trials in the SCI field. Apart from a few notable exceptions such as the NIH effort to replicate promising strategies, this field has been poorly coordinated. Only a small number of articles have even attempted an overall evaluation of the neuroprotective/pharmacotherapy agents used in preclinical SCI trials. There is no consensus about how to select the agents for translation to humans on the basis of their preclinical performance and according to agreed-upon preclinical performance criteria. In the absence of such a system and to select the next agent for translation, the Consortium has developed a Treatment Strategy Selection Committee, and this committee selected the most promising 5 agents for potential translation. The results show that the preclinical work on these 5 agents has left numerous gaps in knowledge about their preclinical performance and confirm the need for significant changes in preclinical neuroprotection/pharmacotherapy trials in SCI. A recommendation is made for the development and validation of a preclinical scoring system involving worldwide experts in preclinical and clinical SCI.

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Activation of TREK Currents by the Neuroprotective Agent Riluzole in Mouse Sympathetic Neurons

Cited by 41 publications

References 67 publications

The Influence of Cold Temperature on Cellular Excitability of Hippocampal Networks

The Influence of Cold Temperature on Cellular Excitability of Hippocampal Networks

A High-Throughput Functional Screen Identifies Small Molecule Regulators of Temperature- and Mechano-Sensitive K_2P Channels

Translational potential of preclinical trials of neuroprotection through pharmacotherapy for spinal cord injury

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Activation of TREK Currents by the Neuroprotective Agent Riluzole in Mouse Sympathetic Neurons

Cited by 41 publications

References 67 publications

The Influence of Cold Temperature on Cellular Excitability of Hippocampal Networks

The Influence of Cold Temperature on Cellular Excitability of Hippocampal Networks

A High-Throughput Functional Screen Identifies Small Molecule Regulators of Temperature- and Mechano-Sensitive K2P Channels

Translational potential of preclinical trials of neuroprotection through pharmacotherapy for spinal cord injury

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A High-Throughput Functional Screen Identifies Small Molecule Regulators of Temperature- and Mechano-Sensitive K_2P Channels