TREK-1 isoforms generated by alternative translation initiation display different susceptibility to the antidepressant fluoxetine

Eckert, Michaela; Egenberger, Brigitte; Döring, Frank; Wischmeyer, Erhard

doi:10.1016/j.neuropharm.2011.06.020

Cited by 23 publications

(20 citation statements)

References 27 publications

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“…Each of these forms is expressed as proteins in both neurons (Thomas et al, 2008) and recombinant expression systems (Eckert et al, 2011). Thomas et al (2008) describe the N terminus truncated form of TREK1 (TREK1DN) as being regionally and developmentally regulated in a number of different regions of the rat central nervous system.…”

Section: N Terminus Modulates Trek1 Channel Pharmacologymentioning

confidence: 99%

“…Both short and long forms appear to be expressed as proteins in both neurons (Thomas et al, 2008) and recombinant expression systems (Eckert et al, 2011). The alternative translation initiation codon is a methionine that immediately precedes the first transmembrane helix (M1) and results in a complete deletion of the intracellular N terminus of the channel.…”

Section: Introductionmentioning

confidence: 99%

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Influence of the N Terminus on the Biophysical Properties and Pharmacology of TREK1 Potassium Channels

et al. 2014

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TWIK-related K 1 1 (TREK1) potassium channels are members of the two-pore domain potassium channel family and contribute to background potassium conductances in many cell types, where their activity can be regulated by a variety of physiologic and pharmacologic mediators. amine] enhance the activity of TREK1 currents, and we show that BL-1249 is the most potent of these compounds. Alternative translation initiation produces a shorter, N terminus truncated form of TREK1 with a much reduced open probability and a proposed increased permeability to sodium compared with the longer form. We show that both forms of TREK1 can be activated by fenamates and that a number of mutations that affect TREK1 channel gating occlude the action of fenamates but only in the longer form of TREK1. Furthermore, fenamates produce a marked enhancement of current through the shorter, truncated form of TREK1 and reveal a K 1 -selective channel, like the long form. These results provide insight into the mechanism of TREK1 channel activation by fenamates, and, given the role of TREK1 channels in pain, they suggest a novel analgesic mechanism for these compounds.

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Section: N Terminus Modulates Trek1 Channel Pharmacologymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Influence of the N Terminus on the Biophysical Properties and Pharmacology of TREK1 Potassium Channels

et al. 2014

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“…Each of these forms is expressed as proteins in both neurons [94] and expression systems [32]. The alternative translation initiation codon is 42 amino acids upstream from the first methionine in the sequence at the N-terminus of the channel.…”

Section: Fenamatesmentioning

confidence: 99%

Two-pore domain potassium channels: potential therapeutic targets for the treatment of pain

Mathie

Veale

2014

Pflugers Arch - Eur J Physiol

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Recent evidence points to a pivotal contribution of a variety of different potassium channels, including two-pore domain potassium (K2P) channels, in chronic pain processing. Expression of several different K2P channel subunits has been detected in nociceptive dorsal root ganglion neurons and trigeminal ganglion neurons, in particular, TREK1, TREK2, TRESK, TRAAK, TASK3 and TWIK1 channels. Of these, the strongest body of evidence from functional studies highlights the importance of TREK1, TRESK and, recently, TREK2 channels. For example, TREK1 knockout mice are more sensitive than wild-type mice to a number of painful stimuli but less sensitive to morphine-induced analgesia. TRESK knockdown mice show behavioural evidence of increased pain and increased sensitivity to painful pressure. Importantly, familial migraine with aura is associated with a dominant-negative mutation in human TRESK channels. Thus, the functional up-regulation of K2P channel activity may be a useful strategy in the development of new therapies for the treatment of pain. Whilst there are few currently available compounds that selectively and directly enhance the activity of TRESK and TREK2 channels, recent advances have been made in terms of identifying compounds that activate TREK1 channels and in understanding how they might act on the channel. Large-scale bio-informatic approaches and the further development of databases of putative ligands, channel structures and putative ligand binding sites on these structures may form the basis for future experimental strategies to detect novel molecules acting to enhance K2P channel activity that would be useful in the treatment of pain.

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“…Nevertheless, the co-expression of both TREK subtypes in dLGN suggests that inhibition of TREK-1 and activation of TREK-2 by acidification may compensate each other. TREK-1-deficient mice [23] have to be used, and a more detailed analysis of alterative translation initiation [56], which is influencing the pharmacological properties of TREK-1 [16], have to be performed in future studies to clarify the role of these channels in TC neurons.…”

Section: Inhibition Of Task and Trek Channels By Gα Q -Coupled Receptorsmentioning

confidence: 99%

Identification of the muscarinic pathway underlying cessation of sleep-related burst activity in rat thalamocortical relay neurons

Bista

Meuth

Kanyshkova

et al. 2011

Pflugers Arch - Eur J Physiol

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Modulation of the standing outward current (I (SO)) by muscarinic acetylcholine (ACh) receptor (MAChR) stimulation is fundamental for the state-dependent change in activity mode of thalamocortical relay (TC) neurons. Here, we probe the contribution of MAChR subtypes, G proteins, phospholipase C (PLC), and two pore domain K(+) (K(2P)) channels to this signaling cascade. By the use of spadin and A293 as specific blockers, we identify TWIK-related K(+) (TREK)-1 channel as new targets and confirm TWIK-related acid-sensitve K(+) (TASK)-1 channels as known effectors of muscarinic signaling in TC neurons. These findings were confirmed using a high affinity blocker of TASK-3 and TREK-1, namely, tetrahexylammonium chloride. It was found that the effect of muscarinic stimulation was inhibited by M(1)AChR-(pirenzepine, MT-7) and M(3)AChR-specific (4-DAMP) antagonists, phosphoinositide-specific PLCβ (PI-PLC) inhibitors (U73122, ET-18-OCH(3)), but not the phosphatidylcholine-specific PLC (PC-PLC) blocker D609. By comparison, depleting guanosine-5'-triphosphate (GTP) in the intracellular milieu nearly completely abolished the effect of MAChR stimulation. The block of TASK and TREK channels was accompanied by a reduction of the muscarinic effect on I (SO). Current-clamp recordings revealed a membrane depolarization following MAChR stimulation, which was sufficient to switch TC neurons from burst to tonic firing under control conditions but not during block of M(1)AChR/M(3)AChR and in the absence of intracellular GTP. These findings point to a critical role of G proteins and PLC as well as TASK and TREK channels in the muscarinic modulation of thalamic activity modes.

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TREK-1 isoforms generated by alternative translation initiation display different susceptibility to the antidepressant fluoxetine

Cited by 23 publications

References 27 publications

Influence of the N Terminus on the Biophysical Properties and Pharmacology of TREK1 Potassium Channels

Influence of the N Terminus on the Biophysical Properties and Pharmacology of TREK1 Potassium Channels

Two-pore domain potassium channels: potential therapeutic targets for the treatment of pain

Identification of the muscarinic pathway underlying cessation of sleep-related burst activity in rat thalamocortical relay neurons

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