NGS NominatedCELA1,HSPG2, andKCNK5as Candidate Genes for Predisposition to Balkan Endemic Nephropathy

Toncheva, Draga; Mihailova-Hristova, M.; Vazharova, Radoslava; Staneva, Rada; Karachanak, Sena; Dimitrov, Plamen; Simeonov, Valeri; Ivanov, Sergey; Balabanski, Lubomir; Serbezov, Dimitar; Malinov, M.; Stefanovic, V.; Čukuranović, Rade; Polenakovič, Momir; Veličković, Ljubinka Janković; Djordjević, Valentina; Jevtović-Stoimenov, Tatjana; Plaseska‐Karanfilska, Dijana; Galabov, Angel S.; Djonov, Valentin; Dimova, Ivanka

doi:10.1155/2014/920723

Cited by 27 publications

(26 citation statements)

References 33 publications

(30 reference statements)

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“…De Broe, ). It is of interest that a number of patients predisposed to BEN have been shown to carry a mutation of the physiological important renal (Sepúlveda et al , ) two‐pore‐domain potassium (K2P) channel, TASK‐2 (K 2P 5.1) (Toncheva et al , ).…”

Section: Introductionmentioning

confidence: 99%

Aristolochic acid, a plant extract used in the treatment of pain and linked to Balkan endemic nephropathy, is a regulator of K2P channels

Veale

Mathie

2016

British J Pharmacology

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Background and PurposeAristolochic acid (AristA) is found in plants used in traditional medicines to treat pain. We investigated the action of AristA on TREK and TRESK, potassium (K2P) channels, which are potential therapeutic targets in pain. Balkan endemic nephropathy (BEN) is a renal disease associated with AristA consumption. A mutation of TASK‐2 (K2P5.1) channels (T108P) is seen in some patients susceptible to BEN, so we investigated how both this mutation and AristA affected TASK‐2 channels.Experimental ApproachCurrents through wild‐type and mutated human K2P channels expressed in tsA201 cells were measured using whole‐cell patch‐clamp recordings in the presence and absence of AristA.Key ResultsTREK‐1‐ and TREK‐2‐mediated currents were enhanced by AristA (100 μM), whereas TRESK was inhibited. Inhibition of TRESK did not depend on the phosphorylation of key intracellular serines but was completely blocked by mutation of bulky residues in the inner pore (F145A_F352A). The TASK‐2_T108P mutation markedly reduced both current density and ion selectivity. A related mutation (T108C) had similar but less marked effects. External alkalization and application of flufenamic acid enhanced TASK‐2 and TASK‐2_T108C current but did not affect TASK‐2_T108P current. AristA (300 μM) produced a modest enhancement of TASK‐2 current.Conclusions and ImplicationsEnhancement of TREK‐1 and TREK‐2 and inhibition of TRESK by AristA may contribute to therapeutically useful effects of this compound in pain. Whilst AristA is unlikely to interact directly with TASK‐2 channels in BEN, loss of functional TASK‐2 channels may indirectly increase susceptibility to AristA toxicity.

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Section: Introductionmentioning

confidence: 99%

Aristolochic acid, a plant extract used in the treatment of pain and linked to Balkan endemic nephropathy, is a regulator of K2P channels

Veale

Mathie

2016

British J Pharmacology

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“…From a pathophysiological point of view, TASK-2 has been implicated in a predisposition to Balkan endemic nephropathy31 through a dominant negative missense mutation supressing function3233, in the pathogenesis of multiple sclerosis and rheumatoid arthritis in humans34, and in murine inflammatory bowel disease35. TASK-2 is gated by extra- and intracellular pH, changes in cell volume and by Gβγ subunits of G proteins36373839.…”

mentioning

confidence: 99%

Phosphatidylinositol (4,5)-bisphosphate dynamically regulates the K2P background K+ channel TASK-2

Niemeyer

Cid

Paulais³

et al. 2017

Sci Rep

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Two-pore domain K2P K+ channels responsible for the background K+ conductance and the resting membrane potential, are also finely regulated by a variety of chemical, physical and physiological stimuli. Hormones and transmitters acting through Gq protein-coupled receptors (GqPCRs) modulate the activity of various K2P channels but the signalling involved has remained elusive, in particular whether dynamic regulation by membrane PI(4,5)P2, common among other classes of K+ channels, affects K2P channels is controversial. Here we show that K2P K+ channel TASK-2 requires PI(4,5)P2 for activity, a dependence that accounts for its run down in the absence of intracellular ATP and its full recovery by addition of exogenous PI(4,5)P2, its inhibition by low concentrations of polycation PI scavengers, and inhibition by PI(4,5)P2 depletion from the membrane. Comprehensive mutagenesis suggests that PI(4,5)P2 interaction with TASK-2 takes place at C-terminus where three basic aminoacids are identified as being part of a putative binding site.

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“…Certain patients with a predisposition to Balkan endemic nephropathy carry the T108P mutation in TASK-2 (Toncheva et al, 2014); TASK-2 mutant T108P does not generate any significant currents in heterologous expression experiments, and this lack of activity is consistent with a role in Balkan endemic nephropathy (Veale and Mathie, 2016).…”

Section: Task-2 and The K 2p Channel Gating Hypothesesmentioning

confidence: 71%

Gating, Regulation, and Structure in K_2P K⁺ Channels: In Varietate Concordia?

et al. 2016

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1 channels with two pore domains in tandem associate as dimers to produce so-called background conductances that are regulated by a variety of stimuli. Whereas gating in K 2P channels has been poorly understood, recent developments have provided important clues regarding the gating mechanism for this family of proteins. Two modes of gating present in other K 1 channels have been considered. The first is the so-called activation gating that occurs by bundle crossing and the splaying apart of pore-lining helices commanding ion passage. The second mode involves a change in conformation at the selectivity filter (SF), which impedes ion flow at this narrow portion of the conduction pathway and accounts for extracellular pH modulation of several K 2P channels. Although some evidence supports the existence of an activation gate in K 2P channels, recent results suggest that perhaps all stimuli, even those sensed at a distant location in the protein, are also mediated by SF gating. Recently resolved crystal structures of K 2P channels in conductive and nonconductive conformations revealed that the nonconductive state is reached by blockade by a lipid acyl chain that gains access to the channel cavity through intramembrane fenestrations. Here we discuss whether this novel type of gating, proposed so far only for membrane tension gating, might mediate gating in response to other stimuli or whether SF gating is the only type of opening/closing mechanism present in K 2P channels.

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NGS NominatedCELA1,HSPG2, andKCNK5as Candidate Genes for Predisposition to Balkan Endemic Nephropathy

Cited by 27 publications

References 33 publications

Aristolochic acid, a plant extract used in the treatment of pain and linked to Balkan endemic nephropathy, is a regulator of K2P channels

Aristolochic acid, a plant extract used in the treatment of pain and linked to Balkan endemic nephropathy, is a regulator of K2P channels

Phosphatidylinositol (4,5)-bisphosphate dynamically regulates the K2P background K+ channel TASK-2

Gating, Regulation, and Structure in K_2P K⁺ Channels: In Varietate Concordia?

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NGS NominatedCELA1,HSPG2, andKCNK5as Candidate Genes for Predisposition to Balkan Endemic Nephropathy

Cited by 27 publications

References 33 publications

Aristolochic acid, a plant extract used in the treatment of pain and linked to Balkan endemic nephropathy, is a regulator of K2P channels

Aristolochic acid, a plant extract used in the treatment of pain and linked to Balkan endemic nephropathy, is a regulator of K2P channels

Phosphatidylinositol (4,5)-bisphosphate dynamically regulates the K2P background K+ channel TASK-2

Gating, Regulation, and Structure in K2P K+ Channels: In Varietate Concordia?

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Gating, Regulation, and Structure in K_2P K⁺ Channels: In Varietate Concordia?