2-Aminoethoxydiphenyl borate activates the mechanically gated human KCNK channels KCNK 2 (TREK-1), KCNK 4 (TRAAK), and KCNK 10 (TREK-2)

Cabrera-Beltran, Lola Jimena; Beltrán, Madeline; Aguado, Ainhara; Gisselmann, Guenter; Hatt, Hanns

doi:10.3389/fphar.2013.00063

Cited by 24 publications

(18 citation statements)

References 18 publications

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“…Interestingly, the application of 2-APB produced a fast increase of I -30 (71.4 ± 19.3 pA; p = 0.020; Figure 7b), this was a transient effect that slowly decreased in −29.9 ± 9.7 pA (p = 0.037). This was in agreement with 2-APB acting as a TREK-2 activator [51]. The application of BK (250 nM) still reduced I -30 in the presence of 2-APB (−48.3 ± 1.5 pA; p = 5.18 × 10 −6 ; n = 5; Figure 7b), probably reflecting the inhibition of the TREK-2 current, previously activated by 2-APB.…”

Section: Neither Protein Kinase C Nor Ca 2+ Are Involved In the Inhibsupporting

confidence: 83%

PIP2 Mediated Inhibition of TREK Potassium Currents by Bradykinin in Mouse Sympathetic Neurons

Rivas-Ramírez

Reboreda

Rueda‐Ruzafa

et al. 2020

IJMS

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Bradykinin (BK), a hormone inducing pain and inflammation, is known to inhibit potassium M-currents (IM) and to increase the excitability of the superior cervical ganglion (SCG) neurons by activating the Ca2+-calmodulin pathway. M-current is also reduced by muscarinic agonists through the depletion of membrane phosphatidylinositol 4,5-biphosphate (PIP2). Similarly, the activation of muscarinic receptors inhibits the current through two-pore domain potassium channels (K2P) of the “Tandem of pore-domains in a Weakly Inward rectifying K+ channel (TWIK)-related channels” (TREK) subfamily by reducing PIP2 in mouse SCG neurons (mSCG). The aim of this work was to test and characterize the modulation of TREK channels by bradykinin. We used the perforated-patch technique to investigate riluzole (RIL) activated currents in voltage- and current-clamp experiments. RIL is a drug used in the palliative treatment of amyotrophic lateral sclerosis and, in addition to blocking voltage-dependent sodium channels, it also selectively activates the K2P channels of the TREK subfamily. A cell-attached patch-clamp was also used to investigate TREK-2 single channel currents. We report here that BK reduces spike frequency adaptation (SFA), inhibits the riluzole-activated current (IRIL), which flows mainly through TREK-2 channels, by about 45%, and reduces the open probability of identified single TREK-2 channels in cultured mSCG cells. The effect of BK on IRIL was precluded by the bradykinin receptor (B2R) antagonist HOE-140 (d-Arg-[Hyp3, Thi5, d-Tic7, Oic8]BK) but also by diC8PIP2 which prevents PIP2 depletion when phospholipase C (PLC) is activated. On the contrary, antagonizing inositol triphosphate receptors (IP3R) using 2-aminoethoxydiphenylborane (2-APB) or inhibiting protein kinase C (PKC) with bisindolylmaleimide did not affect the inhibition of IRIL by BK. In conclusion, bradykinin inhibits TREK-2 channels through the activation of B2Rs resulting in PIP2 depletion, much like we have demonstrated for muscarinic agonists. This mechanism implies that TREK channels must be relevant for the capture of information about pain and visceral inflammation.

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Section: Neither Protein Kinase C Nor Ca 2+ Are Involved In the Inhibsupporting

confidence: 83%

PIP2 Mediated Inhibition of TREK Potassium Currents by Bradykinin in Mouse Sympathetic Neurons

Rivas-Ramírez

Reboreda

Rueda‐Ruzafa

et al. 2020

IJMS

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“…B), and application of 2‐APB alone (without Oxo‐M) had no significant effect on I RIL amplitude, producing a transient outward current before riluzole administration of 48.8 ± 9.7 pA ( n = 5). This effect may be explained by a small transient activation of TREK‐2 that is unlikely to affect the I RIL (Beltrán et al ., ), as is evident by the failure to affect the negative control.…”

Section: Resultsmentioning

confidence: 92%

Muscarinic modulation of TREK currents in mouse sympathetic superior cervical ganglion neurons

Rivas-Ramírez

Cadaveira-Mosquera

Lamas

et al. 2015

Eur J of Neuroscience

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Muscarinic receptors play a key role in the control of neurotransmission in the autonomic ganglia, which has mainly been ascribed to the regulation of potassium M-currents and voltage-dependent calcium currents. Muscarinic agonists provoke depolarization of the membrane potential and a reduction in spike frequency adaptation in postganglionic neurons, effects that may be explained by M-current inhibition. Here, we report the presence of a riluzole-activated current (IRIL ) that flows through the TREK-2 channels, and that is also inhibited by muscarinic agonists in neurons of the mouse superior cervical ganglion (mSCG). The muscarinic agonist oxotremorine-M (Oxo-M) inhibited the IRIL by 50%, an effect that was abolished by pretreatment with atropine or pirenzepine, but was unaffected in the presence of himbacine. Moreover, these antagonists had similar effects on single-channel TREK-2 currents. IRIL inhibition was unaffected by pretreatment with pertussis toxin. The protein kinase C blocker bisindolylmaleimide did not have an effect, and neither did the inositol triphosphate antagonist 2-aminoethoxydiphenylborane. Nevertheless, the IRIL was markedly attenuated by the phospholipase C (PLC) inhibitor ET-18-OCH3. Finally, the phosphatidylinositol-3-kinase/phosphatidylinositol-4-kinase inhibitor wortmannin strongly attenuated the IRIL , whereas blocking phosphatidylinositol 4,5-bisphosphate (PIP2 ) depletion consistently prevented IRIL inhibition by Oxo-M. These results demonstrate that TREK-2 currents in mSCG neurons are inhibited by muscarinic agonists that activate M1 muscarinic receptors, reducing PIP2 levels via a PLC-dependent pathway. The similarities between the signaling pathways regulating the IRIL and the M-current in the same neurons reflect an important role of this new pathway in the control of autonomic ganglia excitability.

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“…Verapamil and fluoxetine failed to restore K + selectivity (Fig A). Similarly, the TREK‐1 channel activators, 2‐APB (Beltran et al , ) and riluzole (Duprat et al , ), had a reduced affinity and did not rescue I267T selectivity (Fig A) and instead caused an additional depolarization (). However, BL‐1249 (Veale et al , ) fully restored TREK‐1 characteristics (Fig A, B, E and F, and ) and hyperpolarized membrane potentials.…”

Section: Resultsmentioning

confidence: 96%

Sodium permeable and “hypersensitive” TREK ‐1 channels cause ventricular tachycardia

et al. 2017

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In a patient with right ventricular outflow tract (RVOT) tachycardia, we identified a heterozygous point mutation in the selectivity filter of the stretch‐activated K2P potassium channel TREK‐1 (KCNK2 or K2P2.1). This mutation introduces abnormal sodium permeability to TREK‐1. In addition, mutant channels exhibit a hypersensitivity to stretch‐activation, suggesting that the selectivity filter is directly involved in stretch‐induced activation and desensitization. Increased sodium permeability and stretch‐sensitivity of mutant TREK‐1 channels may trigger arrhythmias in areas of the heart with high physical strain such as the RVOT. We present a pharmacological strategy to rescue the selectivity defect of the TREK‐1 pore. Our findings provide important insights for future studies of K2P channel stretch‐activation and the role of TREK‐1 in mechano‐electrical feedback in the heart.

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2-Aminoethoxydiphenyl borate activates the mechanically gated human KCNK channels KCNK 2 (TREK-1), KCNK 4 (TRAAK), and KCNK 10 (TREK-2)

Cited by 24 publications

References 18 publications

PIP2 Mediated Inhibition of TREK Potassium Currents by Bradykinin in Mouse Sympathetic Neurons

PIP2 Mediated Inhibition of TREK Potassium Currents by Bradykinin in Mouse Sympathetic Neurons

Muscarinic modulation of TREK currents in mouse sympathetic superior cervical ganglion neurons

Sodium permeable and “hypersensitive” TREK ‐1 channels cause ventricular tachycardia

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