Polymodal activation of the TREK-2 K2P channel produces structurally distinct open states

McClenaghan, Conor; Schewe, Marcus; Aryal, Prafulla; Carpenter, E.P.; Baukrowitz, Thomas; Tucker, Stephen J.

doi:10.1085/jgp.201611601

Cited by 72 publications

(107 citation statements)

References 32 publications

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“…This is therefore consistent with the lower pressures required for functional activation of TREK-2. Overall this demonstrates that increasing lateral tension quickly expands the bilayer, and that these changes produce a down to up conformational change consistent with our proposed model for mechanogating of K2P channels (Figure 1B) (Dong et al., 2015, McClenaghan et al., 2016). In further agreement with this model, the up state structure (4BW5) exhibits a highly stable conformation when subjected to the P-50 stretch protocol (Figure S1B).…”

Section: Resultsmentioning

confidence: 99%

“…The NFx-bound crystal structure of TREK-2 (4XDL) was used as a guide to place the drug in its binding site and the structure then simulated with and without membrane stretch. As predicted from our previous functional studies (Dong et al., 2015, McClenaghan et al., 2016), the presence of NFx in its binding site in the upper part of the fenestration (Figure 4E) interfered with closure of the interface between M4 and adjacent M2, thus slowing movement toward the up state (Figure 4F). This is also consistent with our previous functional studies which show that NFx markedly slows the kinetics of stretch activation (Dong et al., 2015).…”

Section: Resultsmentioning

confidence: 99%

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Bilayer-Mediated Structural Transitions Control Mechanosensitivity of the TREK-2 K2P Channel

et al. 2017

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SummaryThe mechanosensitive two-pore domain (K2P) K+ channels (TREK-1, TREK-2, and TRAAK) are important for mechanical and thermal nociception. However, the mechanisms underlying their gating by membrane stretch remain controversial. Here we use molecular dynamics simulations to examine their behavior in a lipid bilayer. We show that TREK-2 moves from the “down” to “up” conformation in direct response to membrane stretch, and examine the role of the transmembrane pressure profile in this process. Furthermore, we show how state-dependent interactions with lipids affect the movement of TREK-2, and how stretch influences both the inner pore and selectivity filter. Finally, we present functional studies that demonstrate why direct pore block by lipid tails does not represent the principal mechanism of mechanogating. Overall, this study provides a dynamic structural insight into K2P channel mechanosensitivity and illustrates how the structure of a eukaryotic mechanosensitive ion channel responds to changes in forces within the bilayer.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Bilayer-Mediated Structural Transitions Control Mechanosensitivity of the TREK-2 K2P Channel

et al. 2017

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“…Therefore, while depolarization-induced desensitization may explain observations in roughly a third of desensitized neurons, for the majority we believe a more likely explanation is the possibility that peripheral terminals instead became hyperpolarized through direct and/or indirect actions of one or more ingredients in the inflammatory soup, presumably through increased potassium conductance. For example, TREK2 channels expressed in many C fibers (Acosta et al, 2014), are activated by protons (McClenaghan et al, 2016; Sandoz et al, 2009). Further, it is well known that other mediators in the soup (e.g., bradykinin, prostaglandin E2, histamine, and serotonin) can stimulate production of nitric oxide in a variety of cell types and may thus indirectly activate ATP-sensitive potassium channels in sensory neurons (Chi et al, 2007; Du et al, 2011; Kawano et al, 2009; Zoga et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Profound alteration in cutaneous primary afferent activity produced by inflammatory mediators

Smith‐Edwards

DeBerry

Saloman

et al. 2016

eLife

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Inflammatory pain is thought to arise from increased transmission from nociceptors and recruitment of 'silent' afferents. To evaluate inflammation-induced changes, mice expressing GCaMP3 in cutaneous sensory neurons were generated and neuronal responses to mechanical stimulation in vivo before and after subcutaneous infusion of an 'inflammatory soup' (IS) were imaged in an unanesthetized preparation. Infusion of IS rapidly altered mechanical responsiveness in the majority of neurons. Surprisingly, more cells lost, rather than gained, sensitivity and 'silent' afferents that were mechanically insensitive and gained mechanosensitivity after IS exposure were rare. However, the number of formerly 'silent' afferents that became mechanosensitive was increased five fold when the skin was heated briefly prior to infusion of IS. These findings suggest that pain arising from inflamed skin reflects a dramatic shift in the balance of sensory input, where gains and losses in neuronal populations results in novel output that is ultimately interpreted by the CNS as pain.DOI: http://dx.doi.org/10.7554/eLife.20527.001

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“…Although both the up and down conformations of TREK-2 can be conductive, our previous studies have shown that stretch activation preferentially stabilizes the up conformation, and that this has a positive allosteric effect on the filter gating mechanism (31,33). The precise relationship between the different conformational states of any ion channel and their behavior at the single-channel level is complex and not fully understood, however.…”

Section: Stretch Activation Preferentially Destabilizes a Closed Statmentioning

confidence: 96%

“…We have recently shown how increased (symmetrical) lateral tension within the lipid bilayer induces a structural change in TREK-2 from the "down" state of the channel to the more expanded "up" state conformation (31,33,34). However, unlike the nonselective prokaryotic MS channels, in which stretchinduced expansion dilates the central pore, K2P channels remain highly K + -selective (35).…”

Section: Significancementioning

confidence: 99%

Asymmetric mechanosensitivity in a eukaryotic ion channel

Clausen

Jarerattanachat

Carpenter

et al. 2017

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

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Living organisms perceive and respond to a diverse range of mechanical stimuli. A variety of mechanosensitive ion channels have evolved to facilitate these responses, but the molecular mechanisms underlying their exquisite sensitivity to different forces within the membrane remains unclear. TREK-2 is a mammalian twopore domain (K2P) K + channel important for mechanosensation, and recent studies have shown how increased membrane tension favors a more expanded conformation of the channel within the membrane. These channels respond to a complex range of mechanical stimuli, however, and it is uncertain how differences in tension between the inner and outer leaflets of the membrane contribute to this process. To examine this, we have combined computational approaches with functional studies of oppositely oriented single channels within the same lipid bilayer. Our results reveal how the asymmetric structure of TREK-2 allows it to distinguish a broad profile of forces within the membrane, and illustrate the mechanisms that eukaryotic mechanosensitive ion channels may use to detect and fine-tune their responses to different mechanical stimuli.any forms of sensory perception in higher organisms depend on the rapid conversion of mechanical and physical stimuli into the electrochemical language of nerve and muscle cells (1). These transduction mechanisms often involve "mechanosensitive" (MS) ion channels that are able to rapidly convert physicomechanical stimuli into the electrical signals required for complex physiological responses (e.g., touch, pain, hearing, proprioception), as well those mechanical signals that play key roles in development and cell-cell communication (2). The enormous complexity and diversity of these sensory responses suggests that a variety of molecular mechanisms are likely responsible; for example, while some channels are regulated via physical coupling to proteins of the cytoskeleton and/or cell matrix, others respond directly to changes in lipid membrane tension (3). The precise structural and physical mechanisms underlying these processes remain poorly understood, however (4-6).Our current understanding of how membrane tension directly regulates ion channel gating is largely derived from studies of prokaryotic MS ion channels involved in the control of bacterial turgor pressure (7,8). The open state of these MS channels has a larger cross-sectional area than the closed state within the membrane, and stretch-induced changes in the forces within the bilayer stabilize the expanded open-state conformation. This is commonly referred to as the force-from-lipid principle of mechanosensitivity (9). Similar physical principles are thought to regulate many eukaryotic MS channels (5, 10).Typically, the functional activity of MS ion channels is examined in pipette-based patch-clamp recordings in which negative or positive pressures are used to alter bilayer tension. These pressure changes stretch the membrane to alter the lateral pressure profile, the complex profile of forces that vary with location acro...

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Polymodal activation of the TREK-2 K2P channel produces structurally distinct open states

Cited by 72 publications

References 32 publications

Bilayer-Mediated Structural Transitions Control Mechanosensitivity of the TREK-2 K2P Channel

Bilayer-Mediated Structural Transitions Control Mechanosensitivity of the TREK-2 K2P Channel

Profound alteration in cutaneous primary afferent activity produced by inflammatory mediators

Asymmetric mechanosensitivity in a eukaryotic ion channel

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