Propofol postsynaptically suppresses stellate neuron excitability in the entorhinal cortex by influencing the HCN and TREK-2 channels

Li, Xiaojun; Pan, Ke; Zhu, Dan; Li, Yuping; Tao, Guocai

doi:10.1016/j.neulet.2016.03.014

Cited by 5 publications

(4 citation statements)

References 35 publications

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“…Propofol is a positive gating modulator of prokaryotic Navs that promotes activation-coupled inactivation It has been shown that propofol acts as a positive modulator of various ion channels (Jayakar et al, 2013(Jayakar et al, , 2014Li et al, 2016;Ton et al, 2017), which are presumably responsible for both the desired endpoints and adverse effects of general anesthesia. Propofol depresses brain activity in part through the positive modulation of ionotropic GABA A receptors (Orser et al, 1994;Belelli et al, 1999;Jurd et al, 2003;Zecharia et al, 2009;Woll et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Propofol inhibits prokaryotic voltage-gated Na+ channels by promoting activation-coupled inactivation

Yang

Granata

Eckenhoff

et al. 2018

Journal of General Physiology

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Propofol is widely used in the clinic for the induction and maintenance of general anesthesia. As with most general anesthetics, however, our understanding of its mechanism of action remains incomplete. Local and general anesthetics largely inhibit voltage-gated Na channels (Navs) by inducing an apparent stabilization of the inactivated state, associated in some instances with pore block. To determine the biophysical and molecular basis of propofol action in Navs, we investigated NaChBac and NavMs, two prokaryotic Navs with distinct voltage dependencies and gating kinetics, by whole-cell patch clamp electrophysiology in the absence and presence of propofol at clinically relevant concentrations (2-10 µM). In both Navs, propofol induced a hyperpolarizing shift of the pre-pulse inactivation curve without any significant effects on recovery from inactivation at strongly hyperpolarized voltages, demonstrating that propofol does not stabilize the inactivated state. Moreover, there was no evidence of fast or slow pore block by propofol in a non-inactivating NaChBac mutant (T220A). Propofol also induced hyperpolarizing shifts of the conductance-voltage relationships with negligible effects on the time constants of deactivation at hyperpolarized voltages, indicating that propofol does not stabilize the open state. Instead, propofol decreases the time constants of macroscopic activation and inactivation. Adopting a kinetic scheme of Nav gating that assumes preferential closed-state recovery from inactivation, a 1.7-fold acceleration of the rate constant of activation and a 1.4-fold acceleration of the rate constant of inactivation were sufficient to reproduce experimental observations with computer simulations. In addition, molecular dynamics simulations and molecular docking suggest that propofol binding involves interactions with gating machinery in the S4-S5 linker and external pore regions. Our findings show that propofol is primarily a positive gating modulator of prokaryotic Navs, which ultimately inhibits the channels by promoting activation-coupled inactivation.

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Section: Discussionmentioning

confidence: 99%

Propofol inhibits prokaryotic voltage-gated Na+ channels by promoting activation-coupled inactivation

Yang

Granata

Eckenhoff

et al. 2018

Journal of General Physiology

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“…Propofol is a small lipophilic molecule, which interacts with multiple targets, including several ion channels (Kojima et al, 2015). I h blockade by propofol has been studied in several tissues: hippocampal neurons (Funahashi et al, 2001;Higuchi et al, 2003), area postrema (Funahashi et al, 2004), thalamocortical neurons (Ying et al, 2006;Chen et al, 2009a), and EC (Li et al, 2016). Overall, these studies suggest that I h blockade can contribute substantially to the pharmacological actions of the drug, which seems to involve mainly HCN1 and HCN2 channel isoforms (Ying et al, 2006;Chen et al, 2009a).…”

Section: B Pharmacology Of Hcn Blockade By Exogenous Ligandsmentioning

confidence: 99%

The Hyperpolarization-Activated Cyclic Nucleotide–Gated Channels: from Biophysics to Pharmacology of a Unique Family of Ion Channels

Sartiani

Mannaioni

Masi

et al. 2017

Pharmacological Reviews

115

107

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Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels are important members of the voltage-gated pore loop channels family. They show unique features: they open at hyperpolarizing potential, carry a mixed Na/K current, and are regulated by cyclic nucleotides. Four different isoforms have been cloned (HCN1-4) that can assemble to form homo- or heterotetramers, characterized by different biophysical properties. These proteins are widely distributed throughout the body and involved in different physiologic processes, the most important being the generation of spontaneous electrical activity in the heart and the regulation of synaptic transmission in the brain. Their role in heart rate, neuronal pacemaking, dendritic integration, learning and memory, and visual and pain perceptions has been extensively studied; these channels have been found also in some peripheral tissues, where their functions still need to be fully elucidated. Genetic defects and altered expression of HCN channels are linked to several pathologies, which makes these proteins attractive targets for translational research; at the moment only one drug (ivabradine), which specifically blocks the hyperpolarization-activated current, is clinically available. This review discusses current knowledge about HCN channels, starting from their biophysical properties, origin, and developmental features, to (patho)physiologic role in different tissues and pharmacological modulation, ending with their present and future relevance as drug targets.

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“…In the neocortex and subcortical hippocampus, propofol exerts a direct effect on the cell bodies of excitatory neurons, leading to neuronal hyperpolarization and downregulation of excitability (Xu et al, 2014;Li et al, 2016;Kobayashi and Oi, 2017;Luo et al, 2019). Additionally, propofol can enhance inhibitory inputs, thereby suppressing the activity of these brain regions (Chen et al, 1999;Jeong et al, 2011;Wakita et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…A great deal of effort has gone into dissecting the neural circuitry and molecular targets underlying the effects of intravenous general anesthetics including propofol. Many studies have reported that propofol functions directly through generating a wide range of inhibitory impacts on neocortical regions, such as frontal cortex and entorhinal cortex (Li et al, 2016;Kobayashi and Oi, 2017;Luo et al, 2019). It is widely considered that these inhibitory effects might be attributed to that propofol could activate γ-aminobutyric acid type A receptors (GABA A Rs) and thus increase the inhibitory inputs (Reine et al, 1992;Chen et al, 1999;Jeong et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Propofol-induced anesthesia involves the direct inhibition of glutamatergic neurons in the lateral hypothalamus

Huang,

Xiao,

et al. 2024

Front. Neurosci.

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Propofol is the most widely used intravenous general anesthetic; however, the neuronal circuits that mediate its anesthetic effects are still poorly understood. Glutamatergic neurons in the lateral hypothalamus have been reported to be involved in maintenance of arousal and consciousness. Using Vglut2-Cre transgenic mice, we recorded this group of cells specifically and found that propofol can directly inhibit the glutamatergic neurons, and enhance inhibitory synaptic inputs on these cells, thereby reducing neuronal excitability. Through chemogenetic interventions, we found that inhibition of these neurons increased the duration of propofol-induced anesthesia and reduced movement in the animals after the recovery of right reflex. In contrast, activating this group of cells reduced the duration of propofol anesthesia and increased the animals’ locomotor activity after the recovery of right reflex. These results suggest that propofol-induced anesthesia involves the inhibition of glutamatergic neurons in the lateral hypothalamus.

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Propofol postsynaptically suppresses stellate neuron excitability in the entorhinal cortex by influencing the HCN and TREK-2 channels

Cited by 5 publications

References 35 publications

Propofol inhibits prokaryotic voltage-gated Na+ channels by promoting activation-coupled inactivation

Propofol inhibits prokaryotic voltage-gated Na+ channels by promoting activation-coupled inactivation

The Hyperpolarization-Activated Cyclic Nucleotide–Gated Channels: from Biophysics to Pharmacology of a Unique Family of Ion Channels

Propofol-induced anesthesia involves the direct inhibition of glutamatergic neurons in the lateral hypothalamus

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