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Cited by 10Ion channel regulation and functionAnesthesia and Sedative AgentsAnesthesia and Neurotoxicity Research

HCN1 Channels as Targets for Volatile Anesthetics: Coming to the Fore

Goldstein, Peter A.·2015·Anesthesia & Analgesia
DOI 10.1213/ane.0000000000000871
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Abstract

With their pivotal 1994 review, Franks and Lieb1 compelled those seeking insight into the molecular and cellular mechanisms underlying general anesthesia to focus their attention on a relatively small number of channel proteins. Alas, that article predated the discovery of the 4-member Hcn gene family and their gene products, HCN1 to 4 (hyperpolarization activated, cyclic nucleotide gated) channel proteins. There is now substantial evidence that HCN channels should be included in the list of relevant molecular targets as a wide range of anesthetics, including both inhaled (enflurane, isoflurane, halothane,2–6 and xenon7) and IV (pentobarbital,8 ketamine,9,10 and propofol11–13) agents and adjuncts including the μ-opiate receptor agonist loperamide14,15 and α2-receptor agonists (clonidine and dexmedetomidine16–18) inhibit HCN channel function. Weakly selective for K+ over Na+ and activated by hyperpolarization rather than depolarization, HCN channels are, nonetheless, members of the Kv superfamily.19,20 Unlike most other voltage-gated ion channels, however, HCN channels contain a carboxyl-terminal cyclic nucleotide-binding domain, which, in the absence of cAMP (3’-5’-cyclic adenosine monophosphate), serves to inhibit channel activation, whereas cAMP binding to the cyclic nucleotide-binding domain relieves that inhibition and accelerates channel gating.21 HCN subunits assemble as homotetramers and heterotetramers with only the HCN2/HCN3 combination disfavored and, when activated, the channels conduct an inward current that, depending on the tissue, has been variously denoted as Iq, If, or Ih.22 Originally described as a current (If) responsible for the phase 4 spontaneous depolarization that precedes the cardiac action potential,23 Ih (the preferred term when describing the current in neurons) is now known to be widely distributed and to regulate rhythmic oscillations in the nervous system and subthreshold excitability in peripheral and central neurons through control of the resting membrane potential, input resistance, and synaptic integration.19,24 The contribution of Ih to the generation of oscillatory electrical activity in the central nervous system is of particular relevance, because such activity is thought to be fundamental to learning and memory, sensory perception, sleep/wake transitions, and levels of arousal.25–30 Thus, increasing our understanding of anesthetic interactions with HCN channels is of fundamental importance vis-à-vis our understanding of how general anesthetics might produce the clinically relevant behavioral end points of amnesia and hypnosis. This brings us to the present study by Zhou et al.31 in this issue of Anesthesia and Analgesia. The HCN1 channel isoform is strongly expressed in the cerebral cortex and CA1 region of the hippocampus,32 and enflurane, halothane, and isoflurane have previously been shown to inhibit neuronal Ih as well as the current generated by heterologously expressed HCN1 and HCN2 channels.2–6 Here, Zhou et al. tested the immobilizing, hypnotic, and amnestic effects of isoflurane and sevoflurane in genetically modified mice in which Hcn1 was either globally deleted (HCN1−/−33) or the deletion was restricted to the forebrain (HCN1f/f:cre34) using, respectively, withdrawal to tail clamp, loss of righting reflex (LORR), and fear-potentiated startle reflex as the relevant behavioral assays.31 Withdrawal to tail clamp is the long-standing measure for surgical minimum alveolar concentration (MAC), whereas LORR is considered a reasonable facsimile of drug-induced unconsciousness in rodents. The fear-potentiated startle reflex is a classical conditioned learning paradigm in which the unconditioned response (startle reflex evoked by a brief [50 ms], loud [105 dB] noise) was paired with a conditioning noxious electrical shock (0.4 mA for 100 ms) to the foot; the paired noise—foot shock stimuli were applied in the absence or presence of either isoflurane or sevoflurane at subhypnotic concentrations and the startle response measured with an accelerometer. Testing was performed over 3 days: day 1—baseline (noise only); day 2—paired stimuli in the absence or presence of volatile; and day 3—noise only. In all cases, appropriate control mice were used (HCN1+/+ for the global deletion and HCN1f/f for the forebrain-restricted deletion). Notably, the authors found that for both isoflurane (Fig. 2) and sevoflurane (Fig. 3), the MAC for immobility in response to tail clamp was identical in all 4 groups of animals. This they reasonably interpreted to indicate that HCN1 inhibition by isoflurane or sevoflurane does not contribute to their ability to produce immobility. In contrast, and consistent with the proposition that animals (here, mice) in which a putative molecular target has been either altered to render it insensitive to the drug in question35 or removed in its entirety,10 should be resistant to the effects of that drug, global and forebrain-restricted Hcn1 deletion signifi

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  • HCN channels are sensitive to many volatile and intravenous anesthetics in the clinically relevant dose range.

    “These channels are sensitive to a wide variety of volatile and intravenous anesthetics in the clinically relevant dose range [61].”

    From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [61]

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Authors
Goldstein, P. A.
Affiliations
Weill Cornell Medicine (US)
Corresponding author
Goldstein, Peter A.
ORCID
Goldstein, Peter A.
Venue
Anesthesia & Analgesia
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2015-09
Volume
121
Issue
3
Pages
594-596
ISSN
0003-2999 (ISSN-L)
DOI
10.1213/ane.0000000000000871
OpenAlex
W1175221839
Cited by
10
References
57
Citations by year
2026: 1 · 2025: 1 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 2
FWCI
0.29
Type
journal article
Language
en
Open access
closed
Locations
  • Anesthesia & Analgesia (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Sedative Agents
  • Life Sciences › Neuroscience › Developmental Neuroscience › Anesthesia and Neurotoxicity Research
Keywords
HCN channels, hyperpolarization-activated current, HCN1, volatile anesthetics, general anesthesia mechanism, cyclic nucleotide-binding domain, cyclic AMP, channel gating, anesthetic targets, HCN4, HCN2, HCN3, neural oscillations, resting membrane potential, subunit assembly
MeSH terms
Anesthesia, General, Anesthetics, Animals, Humans, Ion Channels

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