Effects of General Anaesthetics on Ligand-Gated Ion Channels

Abstract

The site at which anaesthetics act within the central nervous system (CNS) has been the subject of research for almost 100 years. Most success has been obtained in defining the physical nature of the site [70]. For example, the well established correlation of anaesthetic potency to fat solubility indicates that the site of action is hydrophobic. Research using anaesthetics with unusual solubility properties (sulphur hexafluoride and carbon tetrafluoride) failed to provide support for the alternative hypothesis that interaction within the aqueous phase of the CNS was responsible for anaesthesia [45,46]. It is now generally agreed that interaction at a hydrophobic site is involved, but debate continues as to whether or not this is within the membrane lipids or at a hydrophobic region within specific proteins. Evidence for the latter view has been provided by the fact that bacterial and firefly luciferases are sensitive to anaesthetics with potency ratios comparable to those of mammalian anaesthesia [21, 22, 32, 42, 43]. However, there is no evidence for a substance related to the luciferases within the mammalian CNS and for the protein model of general anaesthesia to be advanced such a target site must be identified. General anaesthetics may affect signal transmission by altering action potential propagation or synaptic transmission or, indeed, both. At clinically relevant concentrations, general anaesthetics appear primarily to affect synaptic processes [5, 53, 58-61], although impulse conduction in small unmyelinated fibres is reduced [4]. There is some evidence that anaesthetics may inhibit neurotransmitter release also [56], which if it were to occur at an excitatory synapse could produce the necessary depression of synaptic transmission. Anaesthetics also have effects on the postsynaptic neurotransmitter receptor/ion channel complex. Much of the early work concentrated on the nicotinic acetylcholine receptor as a model for ligand-gated ion channels in general. However, attention is now being devoted to the receptors activated by excitatory amino acids, which probably form the majority of the fast excitatory synapses in the CNS, and to the principal inhibitory receptors, activated by yaminobutyric acid (GABA) and glycine.

Synaptic PDZ Domain-mediated Protein Interactions Are Disrupted by Inhalational Anesthetics

“…A number of ion channel targets of inhalational anesthetics have been identified, and prominent among these are the inhibitory GABA A and glycine receptor channels (2,42,(45)(46)(47). Interactions between inhaled anesthetics and excitatory NMDA receptor channels also have been defined (48 -51), although small effects of inhaled anesthetics on NMDA receptors have been reported (47,52).…”

The TASK-1 Two-Pore Domain K+ Channel Is a Molecular Substrate for Neuronal Effects of Inhalation Anesthetics

“…Early hypotheses based on nonspecific interactions of lipid-soluble anesthetics with membrane bilayers have largely given way to the current idea that membrane-associated proteins, particularly ion channels, are specifically modulated by anesthetics (Franks and Lieb, 1994). Indeed, a number of ion channel targets of anesthetics have been identified, and prominent among these are the inhibitory GABA A and glycine receptor channels (Daniels and Smith, 1993;Franks and Lieb, 1994;Mihic et al, 1997). It now seems certain that enhancement of chloride currents gated by GABA and glycine contributes to effects of inhalation anesthetics.…”

“…GABA A and/or glycine receptor channels, especially at high concentrations (Daniels and Smith, 1993;Franks and Lieb, 1994;Mihic et al, 1997). However, we found no evidence for a contribution from those receptors to observed membrane effects of anesthetics in motoneurons; after blocking GABA A and glycine receptors with bicuculline (10 M) and strychnine (30 M), the current induced by high concentrations of halothane (1.25 mM) was not different in magnitude, voltage dependence or reversal potential (n ϭ 7, data not shown).…”

The Quest for a Unified Model of Anesthetic Action

“…28 23,31 this puzzling phenomenon also appeared easiest to explain with unitary lipid-based hypotheses, further reinforcing an already fashionable trend (pressure reversal was later shown to be a mechanistic 'red herring'). 32 For these ancillary reasons, not because of rigorous experimental proof, lipid membranes continued to gain momentum well into the 1970s. In fact, a direct experimental attempt to decide between Stanley Miller's hydrate hypothesis and lipid theories failed to declare a winner.…”