Anesthetic Activation of Central Respiratory Chemoreceptor Neurons Involves Inhibition of a THIK-1-Like Background K+ Current

Lazarenko, Roman M.; Fortuna, Michal G.; Shi, Yingtang; Mulkey, Daniel K.; Takakura, Ana C.; Moreira, Thiago S.; Guyenet, Patrice G.; Bayliss, Douglas A.

doi:10.1523/jneurosci.1956-10.2010

Cited by 71 publications

(88 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Alternatively, such effects could be taking place in inhibitory interneurons that may express Kir3 channels. A recent study showed that isoflurane causes activation of some chemosensory neurons through inhibition of a THIK-1-like K 2 P channel that may be essential in maintaining some respiratory motor control during anesthesia (58). This presents another example of seemingly paradoxical potassium channel inhibi- tion by anesthetics, which may control a specific physiological response.…”

Section: Discussionmentioning

confidence: 99%

G Protein βγ Gating Confers Volatile Anesthetic Inhibition to Kir3 Channels

Styer

Mirshahi

Wang

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

G protein-activated inwardly rectifying potassium (GIRK or Kir3) channels are directly gated by the ␤␥ subunits of G proteins and contribute to inhibitory neurotransmitter signaling pathways. Paradoxically, volatile anesthetics such as halothane inhibit these channels. We find that neuronal Kir3 currents are highly sensitive to inhibition by halothane. Given that Kir3 currents result from increased G␤␥ available to the channels, we asked whether reducing available G␤␥ to the channel would adversely affect halothane inhibition. Remarkably, scavenging G␤␥ using the C-terminal domain of ␤-adrenergic receptor kinase (c␤ARK) resulted in channel activation by halothane. Consistent with this effect, channel mutants that impair G␤␥ activation were also activated by halothane. A single residue, phenylalanine 192, occupies the putative G␤␥ gate of neuronal Kir3.2 channels. Mutation of Phe-192 at the gate to other residues rendered the channel non-responsive, either activated or inhibited by halothane. These data indicated that halothane predominantly interferes with G␤␥-mediated Kir3 currents, such as those functioning during inhibitory synaptic activity. Our report identifies the molecular correlate for anesthetic inhibition of Kir3 channels and highlights the significance of these effects in modulating neurotransmitter-mediated inhibitory signaling.Ion channels that control the excitability of neuronal conduction pathways are important targets for halogenated volatile anesthetics (HVAs) 4 (1, 2). HVAs such as halothane enhance the activity of inhibitory GABA A and glycine receptors and inhibit excitatory channels such as glutamate and nicotinic receptors (3). Several two-pore domain K (K 2 P) channels are activated by HVAs (4 -6). G protein-activated inwardly rectifying potassium (GIRK or Kir3) channels are also involved in inhibitory neurotransmission (7). Although ethanol and chloroform activate Kir3 channels (8, 9), paradoxically HVAs inhibit Kir3 channels (10, 11). Therefore, Kir3 channels present a rare case where an HVA such as halothane impairs inhibitory signaling by an ion channel.The exact mechanism for modulation of ion channels by volatile anesthetics is not fully clear (2). Two residues in the TM2 and TM3 of GABA A participate in regulating the effects of enflurane (12). In nicotinic receptors, sites of action for halothane on tyrosine residues near the channel pore were identified (13). The transmembrane domains in AMPA and NMDA receptors play critical roles in their anesthetics and ethanol sensitivity (14,15). Several sites on various K 2 P channels have been identified that are involved in anesthetic sensitivity (5, 16).Inhibitory neurotransmitters, exemplified by GABA, stimulate G␣ i/o -coupled receptors (17, 18) and liberate G␤␥ that directly activates Kir3 channels (19). Kir3 channels mediate slow inhibitory post-synaptic currents in central neurons, limiting neuronal excitability (7). Kir3-null mice show increased seizure susceptibility (20), hyperalgesia (21), and reduced neurotransmitter-, morphine...

show abstract

Section: Discussionmentioning

confidence: 99%

G Protein βγ Gating Confers Volatile Anesthetic Inhibition to Kir3 Channels

Styer

Mirshahi

Wang

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Interestingly, in anesthetized young rats in vivo these neurons do not show a decrease in discharge frequency after a dose of intravenous morphine sufficient to completely abolish phrenic nerve discharge (469). Similarly, 1-1.3 MAC isoflurane increased the discharge frequency of RTN neurons, likely by activating an unidentified kation channel and by inhibiting a leak K channel (THIK-1), while phrenic nerve discharge was depressed (369). On the other hand, intravenous chloralose-urethane depressed discharge of RTN neurons (369).…”

Section: Effects On Chemoreceptionmentioning

confidence: 97%

Effects of Anesthetics, Sedatives, and Opioids on Ventilatory Control

Stuth

Stucke

Zuperku

2012

Comprehensive Physiology

View full text Add to dashboard Cite

This article provides a comprehensive, up to date summary of the effects of volatile, gaseous, and intravenous anesthetics and opioid agonists on ventilatory control. Emphasis is placed on data from human studies. Further mechanistic insights are provided by in vivo and in vitro data from other mammalian species. The focus is on the effects of clinically relevant agonist concentrations and studies using pharmacological, that is, supraclinical agonist concentrations are de-emphasized or excluded.

show abstract

“…These clinical effects might result from a direct effect upon the pattern generator; alternatively, they could reflect decreased chemoreceptive inputs to the pattern generator (see below). It is important to note that, unlike propofol, volatile anesthetic agents do not themselves result in apnea, an effect likely due to activation of RTN neurons [36].…”

Section: Inhalational Anestheticsmentioning

confidence: 99%

Sources of Inspiration: A Neurophysiologic Framework for Understanding Anesthetic Effects on Ventilatory Control

Czick

Waldman

Gross

2013

Curr Anesthesiol Rep

View full text Add to dashboard Cite

Almost every medication that is presently available to provide sedation, analgesia, or general anesthesia significantly depresses one or more ventilatory control mechanisms. This places patients at risk of developing hypoventilation and hypoxemia during moderate or deep sedation as well as general anesthesia. As the neurophysiologic processes underlying normal ventilatory drive are discovered, new insights into the influence of anesthetics on ventilation have been recognized. More importantly, research into ways to circumvent these effects is underway. For example, drugs such as serotonin agonists and ampakines have been shown to counteract opioidinduced ventilatory depression without reversing the analgesic effect. On the other hand, efforts to identify agents that reverse the respiratory depression associated with propofol and the inhalation anesthetics have been less promising. Until reliable means for reversing drug-induced ventilatory depression are developed, prompt recognition of ventilatory insufficiency and initiation of resuscitative measures remain the keys to patient safety.

show abstract

Anesthetic Activation of Central Respiratory Chemoreceptor Neurons Involves Inhibition of a THIK-1-Like Background K+ Current

Cited by 71 publications

References 35 publications

G Protein βγ Gating Confers Volatile Anesthetic Inhibition to Kir3 Channels

G Protein βγ Gating Confers Volatile Anesthetic Inhibition to Kir3 Channels

Effects of Anesthetics, Sedatives, and Opioids on Ventilatory Control

Sources of Inspiration: A Neurophysiologic Framework for Understanding Anesthetic Effects on Ventilatory Control

Contact Info

Product

Resources

About