Spadin Selectively Antagonizes Arachidonic Acid Activation of TREK-1 Channels

Ma, Ruolin; Lewis, Anthony

doi:10.3389/fphar.2020.00434

Cited by 18 publications

(17 citation statements)

References 40 publications

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“…In several previous lines of studies, spadin was shown to reduce the current mediated by TREK-1 in heterologous systems [ 27 , 43 , 44 ]. Both human and mouse TREK-1 channels are inhibited by spadin at low concentrations [ 27 , 43 , 44 ]. However, these studies show that the effect of spadin on TREK-1 activity is enhanced by arachidonic acid (AA), but spadin effect on basal activity of such channels is unknown.…”

Section: Discussionmentioning

confidence: 99%

Spadin Modulates Astrocytic Passive Conductance via Inhibition of TWIK-1/TREK-1 Heterodimeric Channels

Bae

Choi

Ryoo

et al. 2020

IJMS

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Astrocytes, the most abundant cell type in the brain, are non-excitable cells and play critical roles in brain function. Mature astrocytes typically exhibit a linear current–voltage relationship termed passive conductance, which is believed to enable astrocytes to maintain potassium homeostasis in the brain. We previously demonstrated that TWIK-1/TREK-1 heterodimeric channels mainly contribute to astrocytic passive conductance. However, the molecular identity of astrocytic passive conductance is still controversial and needs to be elucidated. Here, we report that spadin, an inhibitor of TREK-1, can dramatically reduce astrocytic passive conductance in brain slices. A series of gene silencing experiments demonstrated that spadin-sensitive currents are mediated by TWIK-1/TREK-1 heterodimeric channels in cultured astrocytes and hippocampal astrocytes from brain slices. Our study clearly showed that TWIK-1/TREK-1-heterodimeric channels can act as the main molecular machinery of astrocytic passive conductance, and suggested that spadin can be used as a specific inhibitor to control astrocytic passive conductance.

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Section: Discussionmentioning

confidence: 99%

Spadin Modulates Astrocytic Passive Conductance via Inhibition of TWIK-1/TREK-1 Heterodimeric Channels

Bae

Choi

Ryoo

et al. 2020

IJMS

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“…Indeed, the treprostinil inhibited current was greater than the original baseline starting current, pre-BL-1249 treatment. BL-1249 pre-activation of TREK-1 current has been shown to antagonize the effect of the inhibitor, spadin ( Ma and Lewis, 2020 ), a similar effect to that observed for TREK-2 current with the activator ML335 and inhibitor norfluoxetine ( Lolicato et al, 2017 ; Proks et al, 2020 ).…”

Section: Discussionmentioning

confidence: 70%

“…To try and elucidate further how treprostinil might be conferring its inhibitory effects on the TREK channels, we considered a known gain-of-function (GOF) mutation that affects the gating of the channel (Y284A). This amino acid has previously been shown to attenuate the effect of the activator, flufenamic acid (FFA) and the effect of arachidonic acid ( Veale et al, 2014 ; Ma and Lewis, 2020 ) and antagonize the inhibitory effects of norfluoxetine and spadin ( McClenaghan et al, 2016 ; Ma and Lewis, 2020 ). As previously reported ( Veale et al, 2014 ) mutation of Y284 to an alanine in TREK-1, resulted in channels with large outward currents of 95.8 pA pF −1 (95% CI: 74.6 to 117.0, n = 5) which were significantly larger ( p < 0.05, unpaired t -test) than WT TREK-1, 24.2 pA pF −1 (95% CI: 18.3 to 30.1, n = 8) and in agreement with channels having a higher P o ( Proks et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

The Prostacyclin Analogue, Treprostinil, Used in the Treatment of Pulmonary Arterial Hypertension, is a Potent Antagonist of TREK-1 and TREK-2 Potassium Channels

2021

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Pulmonary arterial hypertension (PAH) is an aggressive vascular remodeling disease that carries a high morbidity and mortality rate. Treprostinil (Remodulin) is a stable prostacyclin analogue with potent vasodilatory and anti-proliferative activity, approved by the FDA and WHO as a treatment for PAH. A limitation of this therapy is the severe subcutaneous site pain and other forms of pain experienced by some patients, which can lead to significant non-compliance. TWIK-related potassium channels (TREK-1 and TREK-2) are highly expressed in sensory neurons, where they play a role in regulating sensory neuron excitability. Downregulation, inhibition or mutation of these channels leads to enhanced pain sensitivity. Using whole-cell patch-clamp electrophysiological recordings, we show, for the first time, that treprostinil is a potent antagonist of human TREK-1 and TREK-2 channels but not of TASK-1 channels. An increase in TASK-1 channel current was observed with prolonged incubation, consistent with its therapeutic role in PAH. To investigate treprostinil-induced inhibition of TREK, site-directed mutagenesis of a number of amino acids, identified as important for the action of other regulatory compounds, was carried out. We found that a gain of function mutation of TREK-1 (Y284A) attenuated treprostinil inhibition, while a selective activator of TREK channels, BL-1249, overcame the inhibitory effect of treprostinil. Our data suggests that subcutaneous site pain experienced during treprostinil therapy may result from inhibition of TREK channels near the injection site and that pre-activation of these channels prior to treatment has the potential to alleviate this nociceptive activity.

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“…In addition, we applied spadin as a selective antagonist of TREK‐1 channels to test whether TREK‐1 channels are the target of quercetin. Spadin is an engineered fragment of the natural NTSR3/sortilin propeptide and has been shown to inhibit TREK‐1 channel currents only when pre‐activated with arachidonic acid, but not by BL‐1249 or by CDC (Ma & Lewis, 2020). Given that we observed clear inhibition by spadin of activation by quercetin, the flavonoid presumably shared some mechanisms of action with arachidonic acid.…”

Section: Discussionmentioning

confidence: 99%

Quercetin relieves D‐amphetamine‐induced manic‐like behaviour through activating TREK‐1 potassium channels in mice

Ren

Liu

Guo

et al. 2021

British J Pharmacology

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Background and Purpose: Quercetin is a well-known plant flavonoid with neuroprotective properties. Earlier work suggested it may relieve psychiatric disorders, cognition deficits and memory dysfunction through anti-oxidant and/or radical scavenging mechanisms. In addition, quercetin modulated the physiological function of some ion channels. However, the detailed ionic mechanisms of the bioeffects of quercetin remain unknown. Experimental Approach: Effects of quercetin on neuronal activities in the prefrontal cortex (PFC) and its ionic mechanisms were analysed by calcium imaging using mice bearing a green fluorescent protein, calmodulin, and M13 fusion protein and patch clamp in acute brain slices from C57BL/6 J mice and in HEK 293 cells. The possible ionic mechanism of action of quercetin on D-amphetamine-induced manic-like effects in mice was explored with c-fos staining and the open field behaviour test.Key Results: Quercetin reduced calcium influx triggered by PFC pyramidal neuronal activity. This effect involved increasing the rheobase of neuronal firing through decreasing membrane resistance following quercetin treatment. Spadin, a blocker of TREK-1 potassium channels, also blocked the effect of quercetin on the membrane resistance and neuronal firing. Further, spadin blocked the neuroprotective effects of quercetin. The effects of quercetin on TREK-1 channels could be mimicked by GF109203X, a protein kinase C inhibitor. In vivo, injection of quercetin relieved the manic hyperlocomotion in mice, induced by D-amphetamine. This action was partly alleviated by spadin. Conclusion and Implications:TREK-1 channels are a novel target for quercetin, by inhibiting PKC. This action could contribute to both the neuroprotective and antimanic-like effects.

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Spadin Selectively Antagonizes Arachidonic Acid Activation of TREK-1 Channels

Cited by 18 publications

References 40 publications

Spadin Modulates Astrocytic Passive Conductance via Inhibition of TWIK-1/TREK-1 Heterodimeric Channels

Spadin Modulates Astrocytic Passive Conductance via Inhibition of TWIK-1/TREK-1 Heterodimeric Channels

The Prostacyclin Analogue, Treprostinil, Used in the Treatment of Pulmonary Arterial Hypertension, is a Potent Antagonist of TREK-1 and TREK-2 Potassium Channels

Quercetin relieves D‐amphetamine‐induced manic‐like behaviour through activating TREK‐1 potassium channels in mice

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