Two-pore domain K+ (K2P) channels give rise to leak (also called background) K+ currents. The well-known role of background K+ currents is to stabilize the negative resting membrane potential and c...

/pdf/molecular-background-of-leak-k-currents-two-pore-domain-3xd1km54it.pdf

Molecular Background of Leak K+ Currents: Two-Pore Domain Potassium Channels

Background: We tested the hypothesis that in newborn rats, sevoflurane may cause seizures, neurotoxicity, and impairment in synaptic plasticity— effects that may be diminished by the Na + -K + -2Cl - cotransporter 1 inhibitor, bumetanide. Methods: Electroencephalography, activated caspase-3, and hippocampal long-term potentiation were measured in rats exposed to 2.1 % sevoflurane for 0.5-6 h at postnatal days 4-17 (P4-P17). Results: Arterial blood gas samples drawn at a sevoflurane concentration of 2.1 % showed no evidence of either hypoxia or hypoventilation in spontaneously breathing rats. Higher doses of sevoflurane (e.g., 2.9%) caused respiratory depression. During anesthesia maintenance, the electroencephalography exhibited distinctive episodes of epileptic seizures in 40% of P4-P8 rats. Such seizure-like activity was not detected during anesthesia maintenance in P10-P17 rats. Emergence from 3 h of anesthesia with sevoflurane resulted in tonic/ clonic seizures in some P10-P17 rats but not in P4-P8 rats. Bumetanide (5 μmol/kg, intraperitoneally) significantly decreased seizures in P4-P9 rats but did not affect the emergence seizures in P10-P17 rats. Anesthesia of P4 rats with sevoflurane for 6 h caused a significant increase in activated caspase-3 and impairment of long-term potentiation induction measured at 1 and 14-17 days after exposure to sevoflurane, respectively. Pretreatment of P4 rats with bumetanide nearly abolished the increase in activated caspase-3 but did not alleviate impairment of long-term potentiation. Conclusion: These results support the possibility that excitatory output of sevoflurane-potentiated γ-aminobutyric acid type A/glycine systems may contribute to epileptogenic and neurotoxic effects in early postnatal rats.

/pdf/bumetanide-alleviates-epileptogenic-and-neurotoxic-effects-o4xdxtn0vj.pdf

Bumetanide alleviates epileptogenic and neurotoxic effects of sevoflurane in neonatal rat brain.

Sevoflurane, a volatile anaesthetic agent well-tolerated for inhalation induction, provides a useful opportunity to elucidate the processes whereby halogenated ethers disrupt consciousness and cognition. Multiple molecular targets of sevoflurane have been identified, complementing imaging and electrophysiologic markers for the mechanistically obscure progression from wakefulness to unconsciousness. Recent investigations have more precisely detailed scalp EEG activity during this transition, with practical clinical implications. The relative timing of scalp potentials in frontal and parietal EEG signals suggests that sevoflurane might perturb the propagation of neural information between underlying cortical regions. Spatially distributed brain activity during general anaesthesia has been further investigated with positron emission tomography (PET) and resting-state functional magnetic resonance imaging (fMRI). Combined EEG and PET investigations have identified changes in cerebral blood flow and metabolic activity in frontal, parietal, and thalamic regions during sevoflurane-induced loss of consciousness. More recent fMRI investigations have revealed that sevoflurane weakens the signal correlations among brain regions that share functionality and specialization during wakefulness. In particular, two such resting-state networks have shown progressive breakdown in intracortical and thalamocortical connectivity with increasing anaesthetic concentrations: the Default Mode Network (introspection and episodic memory) and the Ventral Attention Network (orienting of attention to salient feature of the external world). These data support the hypotheses that perturbations in temporally correlated activity across brain regions contribute to the transition between states of sevoflurane sedation and general anaesthesia.

Human neural correlates of sevoflurane-induced unconsciousness.

TWIK-related acid-sensitive potassium (TASK) channels—members of the two pore domain potassium (K2P) channel family—are found in neurons1, cardiomyocytes2–4 and vascular smooth muscle cells5, where they are involved in the regulation of heart rate6, pulmonary artery tone5,7, sleep/wake cycles8 and responses to volatile anaesthetics8–11. K2P channels regulate the resting membrane potential, providing background K+ currents controlled by numerous physiological stimuli12–15. Unlike other K2P channels, TASK channels are able to bind inhibitors with high affinity, exceptional selectivity and very slow compound washout rates. As such, these channels are attractive drug targets, and TASK-1 inhibitors are currently in clinical trials for obstructive sleep apnoea and atrial fibrillation16. In general, potassium channels have an intramembrane vestibule with a selectivity filter situated above and a gate with four parallel helices located below; however, the K2P channels studied so far all lack a lower gate. Here we present the X-ray crystal structure of TASK-1, and show that it contains a lower gate—which we designate as an ‘X-gate’—created by interaction of the two crossed C-terminal M4 transmembrane helices at the vestibule entrance. This structure is formed by six residues (243VLRFMT248) that are essential for responses to volatile anaesthetics10, neurotransmitters13 and G-protein-coupled receptors13. Mutations within the X-gate and the surrounding regions markedly affect both the channel-open probability and the activation of the channel by anaesthetics. Structures of TASK-1 bound to two high-affinity inhibitors show that both compounds bind below the selectivity filter and are trapped in the vestibule by the X-gate, which explains their exceptionally low washout rates. The presence of the X-gate in TASK channels explains many aspects of their physiological and pharmacological behaviour, which will be beneficial for the future development and optimization of TASK modulators for the treatment of heart, lung and sleep disorders. The X-ray crystal structure of the potassium channel TASK-1 reveals the presence of an X-gate, which traps small-molecule inhibitors in the intramembrane vestibule and explains their low washout rates from the channel.

/pdf/a-lower-x-gate-in-task-channels-traps-inhibitors-within-the-13i8nsx1i1.pdf

A lower X-gate in TASK channels traps inhibitors within the vestibule

Tandem two-pore potassium channels (K2Ps) have widespread expression in the central nervous system and periphery where they contribute to background membrane conductance. Some general anaesthetics promote the opening of some of these channels, enhancing potassium currents and thus producing a reduction in neuronal excitability that contributes to the transition to unconsciousness. Similarly, these channels may be recruited during the normal sleep-wake cycle as downstream effectors of wake-promoting neurotransmitters such as noradrenaline, histamine and acetylcholine. These transmitters promote K2P channel closure and thus an increase in neuronal excitability. Our understanding of the roles of these channels in sleep and anaesthesia has been largely informed by the study of mouse K2P knockout lines and what is currently predicted by in vitro electrophysiology and channel structure and gating.

/pdf/the-role-of-k2p-channels-in-anaesthesia-and-sleep-8yxidyy29n.pdf

The role of K2P channels in anaesthesia and sleep

Volatile anesthetics have been shown to activate various two-pore (2P) domain K+ (K2P) channels such as TASK-1 and TREK-1 (TWIK-related acid-sensitive K+ channel), and mice deficient in these chann...

https://www.physiology.org/doi/pdf/10.1152/ajpcell.00100.2007

Differential effects of volatile and intravenous anesthetics on the activity of human TASK-1

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Differential effects of volatile and intravenous anesthetics on the activity of human TASK-1