TREK-1 Regulation by Nitric Oxide and cGMP-dependent Protein Kinase

Koh, Sang Don; Monaghan, Kevin; Sergeant, Gerard P.; Ro, Seungil; Walker, Rebecca L.; Sanders, Kenton M.; Horowitz, Burton

doi:10.1074/jbc.m108125200

Cited by 126 publications

(55 citation statements)

References 30 publications

(25 reference statements)

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“…Stretch-activated K ϩ channels are present in neurons of both the central and the peripheral nervous systems (7)(8)(9), and they also have been described in nonnervous tissue including the heart and gastrointestinal tract (4,(10)(11)(12). In rat atria, the mechanosenstive K ϩ currents decline to a plateau of 20-30% of peak within Ϸ1 s (4).…”

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confidence: 99%

Desensitization of mechano-gated K _2P channels

Honoré

Patel

Chemin

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

129

115

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The neuronal mechano-gated K2P channels TREK-1 and TRAAK show pronounced desensitization within 100 ms of membrane stretch. Desensitization persists in the presence of cytoskeleton disrupting agents, upon patch excision, and when channels are expressed in membrane blebs. Mechanosensitive currents evoked with a variety of complex stimulus protocols were globally fit to a four-state cyclic kinetic model in detailed balance, without the need to introduce adaptation of the stimulus. However, we show that patch stress can be a complex function of time and stimulation history. The kinetic model couples desensitization to activation, so that gentle conditioning stimuli do not cause desensitization. Prestressing the channels with pressure, amphipaths, intracellular acidosis, or the E306A mutation reduces the peak-to-steady-state ratio by changing the preexponential terms of the rate constants, increasing the steady-state current amplitude. The mechanical responsivity can be accounted for by a change of in-plane area of Ϸ2 nm 2 between the closed and open conformations. Desensitization and its regulation by chemical messengers is predicted to condition the physiological role of K2P channels.M ost receptors, including ligand-gated ion channels, desensitize with continuous stimulation. Desensitization is a reversible, use-dependent, form of signal plasticity critical for maintaining the dynamic sensitivity over a wide dynamic range. Desensitization also protects cells from inappropriate persistent activation. Many mechano-gated ion channels desensitize (1-5). There are two basic mechanisms that account for desensitization: adaptation and inactivation. Adaptation refers to the uncoupling of the stimulus from the channel, whereas inactivation refers to a block of the permeation path. In hair cells of the inner ear, deflection opens a mechano-gated channel at the tip of the stereocilium leading to depolarization (6). A fast adaptation mechanism (0.3-5 ms) is attributed to the binding of calcium near the channel after permeation through the open ionic pore (6), i.e., Ca 2ϩ block. A slower adaptation (10-100 ms) occurs when the calcium-dependent molecular motor myosin-1c, which pulls on the channels, slips down the actin cytoskeleton reducing the force applied to the channel (6).Rapid desensitization also occurs in mechanosensitive channels expressed in nonspecialized cells. For instance, the stretchactivated cation channel of Xenopus oocyte opens transiently in response to a step change in patch pressure (5). The decrease in current has been attributed to relaxation of the mechanical stimulus, although as shown in this work, that interpretation may not be a good discriminator. Desensitization of the oocyte channel is fragile and may disappear when patches are repetitively stimulated (5). This fragility was attributed to decoupling of the bilayer from the cytoskeleton (5).Stretch-activated K ϩ channels are present in neurons of both the central and the peripheral nervous systems (7-9), and they also have been described in nonne...

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confidence: 99%

Desensitization of mechano-gated K _2P channels

Honoré

Patel

Chemin

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

129

115

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“…The best studied member of the K 2P family is the mammalian mechanosensitive K 2P 2.1 (KCNK2, TREK-1) channel, expressed at high levels in excitable tissues such as the nervous system (2), heart (3), and smooth muscle (4). K 2P 2.1 channels have attracted increasing interest in recent years as their activity and biophysical properties are strongly regulated by various physical and chemical signals (5).…”

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A Novel Mechanism for Human K2P2.1 Channel Gating

Golan‐Cohen

Ben-Abu

Hen

et al. 2008

Journal of Biological Chemistry

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The mammalian K 2P 2.1 potassium channel (TREK-1, KCNK2) is highly expressed in excitable tissues, where it plays a key role in the cellular mechanisms of neuroprotection, anesthesia, pain perception, and depression. Here, we report that external acidification, within the physiological range, strongly inhibits the human K 2P 2.1 channel by inducing "C-type" closure. We have identified two histidine residues (i.e. His-87 and His-141), located in the first external loop of the channel, that govern the response of the channel to external pH. We demonstrate that these residues are within physical proximity to glutamate 84, homologous to Shaker Glu-418, KcsA Glu-51, and KCNK0 Glu-28 residues, all previously argued to stabilize the outer pore gate in the open conformation by forming hydrogen bonds with poreadjacent residues. We thus propose a novel mechanism for pH sensing in which protonation of His-141 and His-87 generates a local positive charge that serves to draw Glu-84 away from its natural interactions, facilitating the collapse of the selectivity filter region. In accordance with this proposed mechanism, low pH modified K 2P 2.1 selectivity toward potassium. Moreover, the proton-mediated effect was inhibited by external potassium ions and was enhanced by a mutation (S164Y) known to accelerate C-type gating. Furthermore, proton-induced current inhibition was more pronounced at negative potentials. Thus, voltage-dependent C-type gating acceleration by protons represents a novel mechanism for K 2P 2.1 outward rectification.

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“…TREK-1 channels are also up-and down-regulated by neurotransmitters and/or their receptor-associated metabotropic signaling mechanisms. For example, nitric oxide enhances TREK-1 activity by stimulating a cGMP-dependent protein kinase (PKG) 1 mechanism that requires a consensus PKG site, Ser-351, in the distal C terminus of TREK-1 (14). Conversely, activation of G␣ s -coupled receptors causes inhibition of TREK-1 channels via a protein kinase A (PKA)-dependent process involving Ser-333, located near the identified PKG site in the cytoplasmic C terminus of TREK-1 (14,15).…”

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confidence: 99%

“…For example, nitric oxide enhances TREK-1 activity by stimulating a cGMP-dependent protein kinase (PKG) 1 mechanism that requires a consensus PKG site, Ser-351, in the distal C terminus of TREK-1 (14). Conversely, activation of G␣ s -coupled receptors causes inhibition of TREK-1 channels via a protein kinase A (PKA)-dependent process involving Ser-333, located near the identified PKG site in the cytoplasmic C terminus of TREK-1 (14,15). It is also clear that TREK-1 is inhibited by G␣ q -coupled receptors (2,16), although the molecular mechanism underlying channel inhibition is less certain in this case.…”

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confidence: 99%

Sequential Phosphorylation Mediates Receptor- and Kinase-induced Inhibition of TREK-1 Background Potassium Channels

Murbartián

Lei

Sando

et al. 2005

Journal of Biological Chemistry

138

168

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Background potassium channels determine membrane potential and input resistance and serve as prominent effectors for modulatory regulation of cellular excitability. TREK-1 is a two-pore domain background K ؉ channel (KCNK2, K2P2.1) that is sensitive to a variety of physicochemical and humoral factors. In this work, we used a recombinant expression system to show that activation of G␣ q -coupled receptors leads to inhibition of TREK-1 channels via protein kinase C (PKC), and we identified a critical phosphorylation site in a key regulatory domain that mediates inhibition of the channel. In HEK 293 cells co-expressing TREK-1 and either the thyrotropin-releasing hormone receptor (TRHR1) or the Orexin receptor (Orx1R), agonist stimulation induced robust channel inhibition that was suppressed by a bisindolylmaleimide PKC inhibitor but not by a protein kinase A blocker ((R p )-cAMP-S). Channel inhibition by agonists or by direct activators of PKC (phorbol dibutyrate) and PKA (forskolin) was disrupted not only by alanine or aspartate mutations at an identified PKA site (Ser-333) in the C terminus, but also at a more proximal regulatory site in the cytoplasmic C terminus (Ser-300); S333A and S300A mutations enhanced basal TREK-1 current, whereas S333D and S300D substitutions mimicked phosphorylation and strongly diminished currents. When studied in combination, TREK-1 current density was enhanced in S300A/S333D but reduced in S300D/S333A mutant channels. Channel mutants were expressed and appropriately targeted to cell membranes. Together, these data support a sequential phosphorylation model in which receptor-induced kinase activation drives modification at Ser-333 that enables subsequent phosphorylation at Ser-300 to inhibit TREK-1 channel activity.

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TREK-1 Regulation by Nitric Oxide and cGMP-dependent Protein Kinase

Cited by 126 publications

References 30 publications

Desensitization of mechano-gated K _2P channels

Desensitization of mechano-gated K _2P channels

A Novel Mechanism for Human K2P2.1 Channel Gating

Sequential Phosphorylation Mediates Receptor- and Kinase-induced Inhibition of TREK-1 Background Potassium Channels

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TREK-1 Regulation by Nitric Oxide and cGMP-dependent Protein Kinase

Cited by 126 publications

References 30 publications

Desensitization of mechano-gated K 2P channels

Desensitization of mechano-gated K 2P channels

A Novel Mechanism for Human K2P2.1 Channel Gating

Sequential Phosphorylation Mediates Receptor- and Kinase-induced Inhibition of TREK-1 Background Potassium Channels

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Desensitization of mechano-gated K _2P channels

Desensitization of mechano-gated K _2P channels