Antagonistic Effect of a Cytoplasmic Domain on the Basal Activity of Polymodal Potassium Channels

Soussia, Ismail Ben; Choveau, Frank S.; Blin, Sandy; Kim, Eun Jin; Féliciangéli, Sylvain; Chatelain, Franck C.; Kang, Dawon; Bichet, Delphine; Lesage, Florian

doi:10.3389/fnmol.2018.00301

Cited by 27 publications

(40 citation statements)

References 45 publications

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“…In regard to activation mediated by anesthetics, removing TREK‐1 Ct beginning from residue 322 abrogated activation by chloroform or halothane (Figure ), without affecting basal activity. But, removing TREK‐1 Ct starting from residue 298 also abolished basal activity, explainable as it removes the basic residues required in the interactions with PIP2 and functionally crucial (Soussia et al., ). Interestingly, fusing TASK‐1 Ct to the inactive deletant TREK‐1 (deleted from 298) restored basal activity without inducing anesthetic sensitivity, which was not induced even by fusing TASK‐1 Ct to the active deletant mutant TREK‐1 (deleted from 322) (Patel et al., ), suggesting that anesthetic binding locations in TASK and TREK channels are different.…”

Section: Anesthetics Interact In Special and Complex Ways With K2p Chmentioning

confidence: 99%

“…TREK (1 and 2) channels are more active than TRAAK at rest and, simultaneously, exhibit higher sensitivity to fluoxetine. However, TRAAK becomes sensitive when activated by arachidonic acid (AA), pointing at linked channel conformation, basal activity, and blocking sensitivity (Soussia et al., ). The TREK subfamily members are polymodal channels, responding to a wide array of stimuli, most of them being transmitted from the intracellular C‐tail (Ct) through the M4 helix and functionally acting on the C‐type gate near the SF (Bagriantsev, Peyronnet, Clark, Honoré, & Minor, ; Treptow & Klein, ).…”

Section: Trek Subfamily Channels and Their Interactions With Modulatomentioning

confidence: 99%

“…Apart from interaction with phospholipids and regulatory proteins, such inputs include phosphorylation, heat, and intracellular pH sensing (Bagriantsev et al., ; Bagriantsev, Clark, & Minor, ; Schewe et al., ). On the Ct, the proximal carboxy‐terminus (pCt), immediately following the M4 helix, is the main signal regulator, transducer, and sensor of inputs in the intracellular compartment (Soussia et al., ). Interestingly, the pCts of TREK‐1 and TRAAK channels have interchangeable functional activity, inhibiting TRAAK, but activating TREK‐1.…”

Section: Trek Subfamily Channels and Their Interactions With Modulatomentioning

confidence: 99%

“…Swapping TREK and TRAAK pCts revealed that pCts not only control channel activity but, at the same time, mediate sensitivity to fluoxetine, which was also exchangeable. The cause of this effect was narrowed down to a group of three basic residues on TREK‐1 pCt (R329, R330, and R331), conserved in TREK‐2 but not in TRAAK, able to mediate a strong interaction with phosphatidylinositol 4,5‐bisphosphate (PIP2) from the inner membrane leaflet and to elicit basal activation (Soussia et al., ). Although not directly linked to fluoxetine binding, a similar effect is due to another cluster of basic residues (R297, K301, K302, K304, and R311) in TREK‐1 (Chemin et al., ), conserved throughout the TREK subfamily and favorably placed to interact with membrane lipids (Brohawn et al., ; Cabanos, Wang, Han, & Hansen, ; Dong et al., ).…”

Section: Trek Subfamily Channels and Their Interactions With Modulatomentioning

confidence: 99%

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

Șterbuleac

2019

Chem Biol Drug Des

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The K+ ion channels comprising the two‐pore domain (K2P) family have specific biophysical roles in generating the critical regulatory K+ current. Ion flow through K2P channels and, implicitly, channel regulation is mediated by diverse metabolic and physical inputs such as mechanical stimulation, interaction with lipids or endogenous regulators, intra‐ or extracellular pH, and phosphorylation, while their function can be finely tuned by chemical compounds. In the latter category, some drug–channel interactions can lead to side effects or have clinical action, while identifying novel chemical modulators of K2Ps is an area of intense research. Due to their cellular and therapeutic importance, much attention was turned to these channels in recent years and several experimental approaches have pinpointed the molecular determinants of K2P chemical modulation. Given their unique structural features and properties, chemical modulators act on K2P channels in multiple and diverse ways. In this review, the particularities of K2P modulation by chemical compounds, such as binding modality, affinity, or position, are identified, synthesized, and linked to structural and functional properties in order to refer to how activators and blockers modify channel function and vice versa, focusing on specificity related to protein structure (and its modification) and cross‐linking information among different subfamilies.

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Section: Anesthetics Interact In Special and Complex Ways With K2p Chmentioning

confidence: 99%

Section: Trek Subfamily Channels and Their Interactions With Modulatomentioning

confidence: 99%

Section: Trek Subfamily Channels and Their Interactions With Modulatomentioning

confidence: 99%

Section: Trek Subfamily Channels and Their Interactions With Modulatomentioning

confidence: 99%

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

Șterbuleac

2019

Chem Biol Drug Des

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“…As for the low basal activity, tonic inhibition by the physiological level of phosphatidylinositol 4,5-bisphosphate (PIP 2 ) has been suggested as the key mechanism including our previous studies ( Fig. 1A ) [ 8 - 14 ].…”

Section: Introductionmentioning

confidence: 96%

Dual regulatory effects of PI(4,5)P₂ on TREK-2 K⁺ channel through antagonizing interaction between the alkaline residues (K³³⁰ and R^355-357) in the cytosolic C-terminal helix

Kim

Woo

et al. 2020

Korean J Physiol Pharmacol

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TWIK-related two-pore domain K + channel-2 (TREK-2) has voltage-independent activity and shows additional activation by acidic intracellular pH (pH i ) via neutralizing the E 332 in the cytoplasmic C terminal (Ct). We reported opposite regulations of TREK-2 by phosphatidylinositol 4,5-bisphosphate (PIP 2 ) via the alkaline K 330 and triple Arg residues (R 355-357 ); inhibition and activation, respectively. The G 334 between them appeared critical because its mutation (G 334 A) endowed hTREK-2 with tonic activity, similar to the mutation of the inhibitory K 330 (K 330 A). To further elucidate the role of putative bent conformation at G 334 , we compared the dual mutation forms, K 330 A/G 334 A and G 334 A/R 355-7 A, showing higher and lower basal activity, respectively. The results suggested that the tonic activity of G 334 A owes to a dominant influence from R 355-7 . Since there are additional triple Arg residues (R 377-9 ) distal to R 355-7 , we also examined the triple mutant (G 334 A/R 355-7 A/R 377-9 A) that showed tonic inhibition same with G 334 A/R 355-7 A. Despite the state of tonic inhibition, the activation by acidic pH i was preserved in both G 334 A/R 355-7 A and G 334 A/R 355-7 A/R 377-9 A, similar to the R 355-7 A. Also, the inhibitory effect of ATP could be commonly demonstrated under the activation by acidic pH i in R 355-7 A, G 334 A/R 355-7 A, and G 334 A/R 355-7 A/R 377-9 A. These results suggest that the putative bent conformation at G 334 is important to set the tug-of-war between K 330 and R 355-7 in the PIP 2 -dependent regulation of TREK-2.

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A standardised hERG phenotyping pipeline to evaluate KCNH2 genetic variant pathogenicity

Oliveira-Mendes

Féliciangéli

Ménard

et al. 2021

Clinical & Translational Med

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Background and aims Mutations in KCNH2 cause long or short QT syndromes (LQTS or SQTS) predisposing to life‐threatening arrhythmias. Over 1000 hERG variants have been described by clinicians, but most remain to be characterised. The objective is to standardise and accelerate the phenotyping process to contribute to clinician diagnosis and patient counselling. In silico evaluation was also included to characterise the structural impact of the variants. Methods We selected 11 variants from known LQTS patients and two variants for which diagnosis was problematic. Using the Gibson assembly strategy, we efficiently introduced mutations in hERG cDNA despite GC‐rich sequences. A pH‐sensitive fluorescent tag was fused to hERG for efficient evaluation of channel trafficking. An optimised 35‐s patch‐clamp protocol was developed to evaluate hERG channel activity in transfected cells. R software was used to speed up analyses. Results In the present work, we observed a good correlation between cell surface expression, assessed by the pH‐sensitive tag, and current densities. Also, we showed that the new biophysical protocol allows a significant gain of time in recording ion channel properties and provides extensive information on WT and variant channel biophysical parameters, that can all be recapitulated in a single parameter defined herein as the repolarisation power. The impacts of the variants on channel structure were also reported where structural information was available. These three readouts (trafficking, repolarisation power and structural impact) define three pathogenicity indexes that may help clinical diagnosis. Conclusions Fast‐track characterisation of KCNH2 genetic variants shows its relevance to discriminate mutants that affect hERG channel activity from variants with undetectable effects. It also helped the diagnosis of two new variants. This information is meant to fill a patient database, as a basis for personalised medicine. The next steps will be to further accelerate the process using an automated patch‐clamp system.

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Antagonistic Effect of a Cytoplasmic Domain on the Basal Activity of Polymodal Potassium Channels

Cited by 27 publications

References 45 publications

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

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

Dual regulatory effects of PI(4,5)P₂ on TREK-2 K⁺ channel through antagonizing interaction between the alkaline residues (K³³⁰ and R^355-357) in the cytosolic C-terminal helix

A standardised hERG phenotyping pipeline to evaluate KCNH2 genetic variant pathogenicity

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Antagonistic Effect of a Cytoplasmic Domain on the Basal Activity of Polymodal Potassium Channels

Cited by 27 publications

References 45 publications

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

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

Dual regulatory effects of PI(4,5)P2 on TREK-2 K+ channel through antagonizing interaction between the alkaline residues (K330 and R355-357) in the cytosolic C-terminal helix

A standardised hERG phenotyping pipeline to evaluate KCNH2 genetic variant pathogenicity

Contact Info

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Resources

About

Dual regulatory effects of PI(4,5)P₂ on TREK-2 K⁺ channel through antagonizing interaction between the alkaline residues (K³³⁰ and R^355-357) in the cytosolic C-terminal helix