Classification of 2-pore domain potassium channels based on rectification under quasi-physiological ionic conditions

Chen, Haijun; Zuo, Dongchuan; Zhang, Jianing; Zhou, Min; Ma, Liqun

doi:10.4161/19336950.2014.973779

Cited by 6 publications

(7 citation statements)

References 22 publications

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“…17 The third and final channel studied belongs to the two pore domain potassium (K2P) channels, which generate leak potassium currents, and thus plays an essential role in cell excitability. K2P channels have been proposed to show weak inward rectification, [18][19] suggesting resemblance with/to inward-rectifying (Kir) potassium channels. 19 Six subfamilies, TWIK, TREK, TALK, TASK, THIK, and TRESK have been identified, primarily implicated in a range of cardiovascular and neurological disorders.…”

Section: Introductionmentioning

confidence: 99%

Lateral Fenestrations in K⁺-Channels Explored Using Molecular Dynamics Simulations

et al. 2016

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Potassium channels are of paramount physiological and pathological importance and therefore constitute significant drug targets. One of the keys to rationalize the way drugs modulate ion channels is to understand the ability of such small molecules to access their respective binding sites, from which they can exert an activating or inhibitory effect. Many computational studies have probed the energetics of ion permeation, and the mechanisms of voltage gating, but little is known about the role of fenestrations as possible mediators of drug entry in potassium channels. To explore the existence, structure, and conformational dynamics of transmembrane fenestrations accessible by drugs in potassium channels, molecular dynamics simulation trajectories were analyzed from three potassium channels: the open state voltage-gated channel Kv1.2, the G protein-gated inward rectifying channel GIRK2 (Kir3.2), and the human two-pore domain TWIK-1 (K2P1.1). The main results of this work were the identification of the sequence identity of four main lateral fenestrations of similar length and with bottleneck radius in the range of 0.9-2.4 Å for this set of potassium channels. It was found that the fenestrations in Kv1.2 and Kir3.2 remain closed to the passage of molecules larger than water. In contrast, in the TWIK-1 channel, both open and closed fenestrations are sampled throughout the simulation, with bottleneck radius shown to correlate with the random entry of lipid membrane molecules into the aperture of the fenestrations. Druggability scoring function analysis of the fenestration regions suggests that Kv and Kir channels studied are not druggable in practice due to steric constraining of the fenestration bottleneck. A high (>50%) fenestration sequence identity was found in each potassium channel subfamily studied, Kv1, Kir3, and K2P1. Finally, the reported fenestration sequence of TWIK-1 compared favorably with another channel, K2P channel TREK-2, reported to possess open fenestrations, suggesting that K2P channels could be druggable via fenestrations, for which we reported atomistic detail of the fenestration region, including the flexible residues M260 and L264 that interact with POPC membrane in a concerted fashion with the aperture and closure of the fenestrations.

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Section: Introductionmentioning

confidence: 99%

Lateral Fenestrations in K⁺-Channels Explored Using Molecular Dynamics Simulations

et al. 2016

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“…Quantitative studies summarizing the properties of macroscopic currents through the glial Kir4.1 (Seifert G., 2018) and K2P-TREK channels (Schewe et al, 2016), (Chen, 2014) suggest that apart from K2P activation there is no other channel kinetics critical to extend (13) with additional dynamical variable. Whole-cell Kir4.1 currents were showing rise times of less than 2 ms and negligible difference between the peak and steady current levels, in the mid-range voltages V m where the interaction of different currents is dynamically interesting.…”

Section: Resultsmentioning

confidence: 99%

“…Figure 5A shows pharmacologically isolated K2P current, using quinine , at [ K + ] o , = 5 mM (black circles), as well as at drastically elevated external potassium at [ K + ] o = 50 mM (blue dots) in our data from (Seifert et al, 2009). Both I-V recordings were fitted (solid lines) with the standard GHK current equation (Chen, 2014), even though the permeation studies suggest multi-ion occupancy of the pore and some form of pseudo gating (Schewe et al, 2016). Adding a small Na + permeability (Chen, 2014), P Na /P K = 0.06, within nominally non-conductive range (below −50 mV ) improves the fit at 5 mM , solid purple line.…”

Section: Model Of Astroglial Whole-cell Vm Dynamicsmentioning

confidence: 99%

“…Both I-V recordings were fitted (solid lines) with the standard GHK current equation (Chen, 2014), even though the permeation studies suggest multi-ion occupancy of the pore and some form of pseudo gating (Schewe et al, 2016). Adding a small Na + permeability (Chen, 2014), P Na /P K = 0.06, within nominally non-conductive range (below −50 mV ) improves the fit at 5 mM , solid purple line. That effect of Na + on passive K + conductivity in glia is known (Ransom & Goldring, 1973), but we didn’t use the correction within the numerical simulations due to a lack of recordings to verify P Na /P K dependence itself on [ K + ] o for notably elevated levels above 5 mM.…”

Section: Model Of Astroglial Whole-cell Vm Dynamicsmentioning

confidence: 99%

“…Along with these observations we model the astrocytic K2P-TREK1 currents using the GHK current model (Chen, 2014), extended with electrochemically dependent activation n K 2 P – coupling the voltage-dependent activation and electrochemical driving force into a mechanism named ion-flux gating (Schewe et al, 2016): …”

Section: Model Of Astroglial Whole-cell Vm Dynamicsmentioning

confidence: 99%

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Non-trivial dynamics in a model of glial membrane voltage driven by open potassium pores

Janjic

Solev

Kocarev

2022

Preprint

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Despite the molecular evidence that close to linear steady state current-voltage relationship in mammalian astrocytes reflects a total current resulting from more than one differently regulated K+ conductances, detailed ODE models of membrane voltage Vm incorporating multiple conductances are still lacking. Repeated experimental results of deregulated expressions of major K+ channels in glia, Kir4.1, in models of neurodegenerative disease, as well as their altered rectification when assembling heteromeric Kir4.1/Kir5.1 channels have motivated us to attempt a detailed model incorporating the weaker potassium K2P TREK1 current, in addition to Kir4.1, and study the stability of the resting state Vr. The main question is whether with a deregulated Kir conductivity the nominal resting state Vr remains stable, and the cell retains a potassium electrode behavior with Vm following E_K. The minimal 2-dimensional model near Vr showed that certain alterations of Kir4.1 current may result in multistability of Vm if the model incorporates the typically observed K+ currents: Kir, K2P, and non-specific potassium leak. More specifically, a decrease or loss of outward Kir4.1 conductance (turning the channels into inwardly rectifying) introduces instability of Vr, near E_K. That happens through robustly observed fold bifurcation giving birth to a much more depolarized second, stable resting state Vdr > (neg)10 mV. Realistic time series were used to perturb the membrane model, from recordings at the glial membrane during electrographic seizures. Simulations of the perturbed system by constant currents through gap-junctions and transient seizurelike discharges as local field potentials led to depolarization of the astrocyte and switching of Vm between the two stable states, in a "down state / up state" manner. If the prolonged depolarizations near Vdr prove experimentally plausible, such catastrophic instability would impact all aspects of the glial function, from metabolic support to membrane transport and practically all neuromodulatory roles assigned to glia.

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Unraveling the Molecular Reason of Opposing Effects of α‐Mangostin and Norfluoxetine on TREK‐2 at the Same Binding Site

Kim,

Van,

Nam

et al. 2024

ChemMedChem

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TWIK‐related K(+) channel (TREK)‐2, expressed in sensory neurons, is involved in setting membrane potential, and its modulations contributes to the generation of nociceptive signals. Although acute and chronic pain is a common symptom experienced by patients with various conditions, most existing analgesics exhibit low efficacy and are associated with adverse effects. For this reason, finding the novel modulator of TREK‐2 is of significance for the development of new analgesics. Recent studies have shown that α‐Mangostin (α‐MG) activates TREK‐2, facilitating analgesic effects, yet the underlying molecular mechanisms remain elusive. Intriguingly, even though norfluoxetine (NFx) is known to inhibit TREK‐2, α‐MG is also observed to share the same binding site with NFx, and this implies that TREK‐2 might be modulated in a highly complicated manner. Therefore, we examine the mechanism of how TREK‐2 is activated by α‐MG using computational methods and patch clamp experiments in the present study. Based on these results, we offer an explanation of how α‐MG and NFx exhibit opposing effects at the same binding site of TREK‐2. These findings will broaden our understanding of TREK‐2 modulation, providing clues for designing novel analgesic drugs.

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Classification of 2-pore domain potassium channels based on rectification under quasi-physiological ionic conditions

Abstract: (2014) Classification of 2-pore domain potassium channels based on rectification under quasiphysiological ionic conditions, Channels, 8:6,[503][504][505][506][507][508]

Cited by 6 publications

References 22 publications

Lateral Fenestrations in K⁺-Channels Explored Using Molecular Dynamics Simulations

Lateral Fenestrations in K⁺-Channels Explored Using Molecular Dynamics Simulations

Non-trivial dynamics in a model of glial membrane voltage driven by open potassium pores

Unraveling the Molecular Reason of Opposing Effects of α‐Mangostin and Norfluoxetine on TREK‐2 at the Same Binding Site

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Classification of 2-pore domain potassium channels based on rectification under quasi-physiological ionic conditions

Abstract: (2014) Classification of 2-pore domain potassium channels based on rectification under quasiphysiological ionic conditions, Channels, 8:6,[503][504][505][506][507][508]

Cited by 6 publications

References 22 publications

Lateral Fenestrations in K+-Channels Explored Using Molecular Dynamics Simulations

Lateral Fenestrations in K+-Channels Explored Using Molecular Dynamics Simulations

Non-trivial dynamics in a model of glial membrane voltage driven by open potassium pores

Unraveling the Molecular Reason of Opposing Effects of α‐Mangostin and Norfluoxetine on TREK‐2 at the Same Binding Site

Contact Info

Product

Resources

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Lateral Fenestrations in K⁺-Channels Explored Using Molecular Dynamics Simulations

Lateral Fenestrations in K⁺-Channels Explored Using Molecular Dynamics Simulations