Science
 2015
DOI: 10.1126/science.1261512
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K2P channel gating mechanisms revealed by structures of TREK-2 and a complex with Prozac

Yin Yao Dong
1
,
A.C.W. Pike
2
,
Alexandra Mackenzie
3
et al.

Abstract: TREK-2 (KCNK10/K2P10), a two-pore domain potassium (K2P) channel, is gated by multiple stimuli such as stretch, fatty acids, and pH and by several drugs. However, the mechanisms that control channel gating are unclear. Here we present crystal structures of the human TREK-2 channel (up to 3.4 angstrom resolution) in two conformations and in complex with norfluoxetine, the active metabolite of fluoxetine (Prozac) and a state-dependent blocker of TREK channels. Norfluoxetine binds within intramembrane fenestratio… Show more

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Cited by 306 publications

(608 citation statements)
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“…It thus appears that the conservation pattern of these residues may be connected to their role in mechanosensing but the correspondence is not strict, rendering it likely that also other factors contribute. In agreement with our findings, the M322A mutant is already known to show less stretch activation (Dong 2015 ) and the precise role M322 has in stabilizing the “up” state was discussed elsewhere (Aryal 2017 ). In total, 4 of the 10 identified residues (5 most positive and 5 most negative average coefficients) have been experimentally tested as alanine mutants, and all of them showed reduced stretch activation (see Tables S2a,b).…”
Section: Resultssupporting
confidence: 92%
Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.
show abstract
“…It thus appears that the conservation pattern of these residues may be connected to their role in mechanosensing but the correspondence is not strict, rendering it likely that also other factors contribute. In agreement with our findings, the M322A mutant is already known to show less stretch activation (Dong 2015 ) and the precise role M322 has in stabilizing the “up” state was discussed elsewhere (Aryal 2017 ). In total, 4 of the 10 identified residues (5 most positive and 5 most negative average coefficients) have been experimentally tested as alanine mutants, and all of them showed reduced stretch activation (see Tables S2a,b).…”
Section: Resultssupporting
confidence: 92%
Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.
show abstract
“…S3 A – F ). Overall, the molecular architecture of TASK3 is largely consistent with previously reported K2P structures ( 22 , 37 – 42 ). Each protomer in the domain-swapped TASK3 dimer contains two homologous pore-forming domains (PDs).…”
Section: Resultssupporting
confidence: 88%
Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.
show abstract
“…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: Resultssupporting
confidence: 87%
“…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: Resultssupporting
confidence: 87%
Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.
show abstract
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