K2P2.1 (TREK-1) potassium channel activation protects against hyperoxia-induced lung injury

Zyrianova, Tatiana; López, Benjamín; Olcese, Riccardo; Belperio, John A.; Waters, Christopher M.; Wong, Leanne; Nguyen, Victoria; Talapaneni, Sriharsha; Schwingshackl, Andreas

doi:10.1038/s41598-020-78886-y

Cited by 21 publications

(15 citation statements)

References 111 publications

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“…Studies of K 2P function have uncovered that members of this family are important for diverse classes of physiological responses and pathological conditions such as action potential propagation, 15 , 16 anesthetic responses, 17 , 18 microglial surveillance, 19 sleep duration, 20 pain, 21 – 23 arrhythmia, 24 ischemia, 17 , 25 , 26 cardiac fibrosis, 27 depression, 28 migraine, 29 intraocular pressure regulation, 30 pulmonary hypertension, 31 and lung injury. 32 Due to their unusual topology, diverse gating stimuli, and poor pharmacology, K 2P s have remained the most poorly understood potassium channel class. 8 , 9 , 33 – 35 Nevertheless, the structures of six homomeric K 2P s are now known ( Figure 1 (a) ) 36 – 41 and reveal a conserved overall architecture that defines the K 2P family ( Figure 1(c) and (d) ).…”

Section: Introductionmentioning

confidence: 99%

Structural Insights into the Mechanisms and Pharmacology of K2P Potassium Channels

Natale

Deal

Minor

2021

Journal of Molecular Biology

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Leak currents, defined as voltage and time independent flows of ions across cell membranes, are central to cellular electrical excitability control. The K 2P ( KCNK ) potassium channel class comprises an ion channel family that produces potassium leak currents that oppose excitation and stabilize the resting membrane potential in cells in the brain, cardiovascular system, immune system, and sensory organs. Due to their widespread tissue distribution, K 2P s contribute to many physiological and pathophysiological processes including anesthesia, pain, arrythmias, ischemia, hypertension, migraine, intraocular pressure regulation, and lung injury responses. Structural studies of six homomeric K 2P s have established the basic architecture of this channel family, revealed key moving parts involved in K 2P function, uncovered the importance of asymmetric pinching and dilation motions in the K 2P selectivity filter (SF) C-type gate, and defined two K 2P structural classes based on the absence or presence of an intracellular gate. Further, a series of structures characterizing K 2P :modulator interactions have revealed a striking polysite pharmacology housed within a relatively modestly sized (~70 kDa) channel. Binding sites for small molecules or lipids that control channel function are found at every layer of the channel structure, starting from its extracellular side through the portion that interacts with the membrane bilayer inner leaflet. This framework provides the basis for understanding how gating cues sensed by different channel parts control function and how small molecules and lipids modulate K 2P activity. Such knowledge should catalyze development of new K 2P modulators to probe function and treat a wide range of disorders.

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Section: Introductionmentioning

confidence: 99%

Structural Insights into the Mechanisms and Pharmacology of K2P Potassium Channels

Natale

Deal

Minor

2021

Journal of Molecular Biology

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“…In principle, the resulting tensions of the cell membranes may activate mechanosensitive channels. TREK-1 was reported to be expressed in alveolar epithelial cells [182,183], contribute to the reaction to hyperoxia [184,185], and modulate inflammatory mediator (interleukin-6, monocyte chemotactic protein-1) release [186,187]. It has also been suggested that TREK-1 modulates stretch-induced detachment of alveolar epithelial cells [188].…”

Section: Physiological Role Of the Mechanical Activation Of K 2p Channels In Other Locationsmentioning

confidence: 99%

Negative Influence by the Force: Mechanically Induced Hyperpolarization via K2P Background Potassium Channels

Lengyel

Enyedi

Czirják

2021

IJMS

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The two-pore domain K2P subunits form background (leak) potassium channels, which are characterized by constitutive, although not necessarily constant activity, at all membrane potential values. Among the fifteen pore-forming K2P subunits encoded by the KCNK genes, the three members of the TREK subfamily, TREK-1, TREK-2, and TRAAK are mechanosensitive ion channels. Mechanically induced opening of these channels generally results in outward K+ current under physiological conditions, with consequent hyperpolarization and inhibition of membrane potential-dependent cellular functions. In the past decade, great advances have been made in the investigation of the molecular determinants of mechanosensation, and members of the TREK subfamily have emerged among the best-understood examples of mammalian ion channels directly influenced by the tension of the phospholipid bilayer. In parallel, the crucial contribution of mechano-gated TREK channels to the regulation of membrane potential in several cell types has been reported. In this review, we summarize the general principles underlying the mechanical activation of K2P channels, and focus on the physiological roles of mechanically induced hyperpolarization.

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“…Furthermore, BL1249 has previously been validated to be specifically active in the TREK-1 channel, not only in heterologous expression systems but also in primary cells (20,21), which act on a gating mechanism involving a site located below the selectivity filter and the C-type gate (2). However, there is no study investigating whether bepridil can affect BL1249-activated TREK-1 current.…”

Section: Original Articlementioning

confidence: 99%

Bepridil, a class IV antiarrhythmic agent, can block the TREK-1 potassium channel

Wang

et al. 2021

Ann Transl Med

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Background: The TWIK-related potassium channel (TREK-1) can be regulated by different stimuli. However, it is not clear whether some antiarrhythmics affect the activity of TREK-1. In the present study, the effect of bepridil on the TREK-1 currents is investigated.Methods: In a TREK-1 stably-expressed HEK-293 cell line (HEK-TREK-1), U251MG cells, and isolated mouse ventricular myocytes, the TREK-1 current and action potentials were recorded by the patch-clamp technique. The standard voltage protocol was a 200 ms constant potential at 20 mV, followed bya 500 ms ramp from -90 to +20 mV (HEK-TREK-1) or +80 mV (U251MG cells and myocytes) every 10 s. The currents at +20 mV or +80 mV were used for analysis. The docking study of bepridil's binding model in the TREK-1 channel was performed using the Swissdock web service.Results: In HEK-TREK-1 cells, BL1249 induced a significantly large outwardly rectifying current with similar baseline TREK-1 current characteristic, with a reversal potential (−70 mV). The concentration of half-maximal activation (EC 50 ) of BL1249 was 3.45 µM. However, bepridil decreased the baseline TREK-1 currents, with a concentration of half-maximal inhibition (IC 50 ) 0.59 µM and a Hill coefficient of 1.1. Also, bepridil inhibited BL1249-activated TREK-1 currents, with an IC 50 4.08 µM and a Hill coefficient of 3.22. The outside-out patch-clamp confirmed bepridil inhibited BL1249-activated TREK-1 currents. In U251MG cells and myocytes, BL1249 activated outwardly rectifying endogenous TREK-1 currents, which could be inhibited by bepridil. BL1249 (10 µM) could decrease the peak value and reduce the duration of the action potential. Bepridil (10 µM) prolonged the duration of action potential of myocytes. The docking study revealed that bepridil might affect the K + pore domain and the M4 modulator pocket.Conclusions: Bepridil may be a blocker for the TREK-1K + channel at a clinically therapeutic concentration, providing a new mechanism of TREK-1 regulation and bepridil's antiarrhythmic effect.

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K2P2.1 (TREK-1) potassium channel activation protects against hyperoxia-induced lung injury

Cited by 21 publications

References 111 publications

Structural Insights into the Mechanisms and Pharmacology of K2P Potassium Channels

Structural Insights into the Mechanisms and Pharmacology of K2P Potassium Channels

Negative Influence by the Force: Mechanically Induced Hyperpolarization via K2P Background Potassium Channels

Bepridil, a class IV antiarrhythmic agent, can block the TREK-1 potassium channel

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