Ion channels are a likely target of anesthetic action.

1. Anesthetic Effects on Voltage-Dependent Ion Channels. A variety of ion channels can sense a change in membrane potential and respond by either opening or closing their pores.
   1. Voltage-dependent calcium channels serve to couple electrical activity to specific cellular functions (respond to action potentials by opening). This allows calcium to enter the cell, activating calcium-dependent secretion of neurotransmitter into the synaptic cleft.
   2. Potassium channels are the most diverse of the ion channel types and include voltage-gated (background or leak channels) that open over a wide-range of voltages.
2. Anesthetic Effects on Ligand-Gated Ion Channels. Fast excitatory and inhibitory neurotransmission is mediated by the actions of ligand-gated ion channels. Synaptically released glutamate or GABA (γ-aminobutyric acid) diffuse across the synaptic cleft and bind to channel proteins that open as a consequence of neurotransmitter release. The ligand-gated ion channels provide a logical target for anesthetic action because selective effects on these channels could inhibit fast excitatory synaptic transmission or facilitate fast inhibitory synaptic transmission.
   1. Glutamate-Activated Ion Channels (AMPA [AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid] receptors, kainate receptors, NMDA [N-methyl-D-aspartic acid] receptors)
      1. AMPA and kainate receptors are relatively nonselective monovalent cation channels involved in fast excitatory synaptic transmission.
      2. NMDA channels conduct not only Na⁺ and K⁺ but also Ca⁺⁺ and are involved in long-term modulation of synaptic responses (long-term potentiation). NMDA-activated currents also appear to be sensitive to a subset of anesthetics.
      3. Ketamine is a potent and selective inhibitor of NMDA-activated currents. Ketamine stereoselectively inhibits NMDA currents by binding to the phencyclidine site on the NMDA receptor protein.
      4. NMDA receptors may also be an important target for nitrous oxide and xenon.
   2. GABA-Activated Ion Channels. GABA is the most important inhibitory neurotransmitter in the mammalian CNS.
      1. GABA-activated ion channels (GABA_A receptors) mediate the postsynaptic response to synaptically released GABA by selectively allowing chloride ions to enter and thereby hyperpolarize neurons. GABA_A receptors are multisubunit proteins consisting of various combinations of α, β, δ, and ε subunits, and there are many subtypes of each of these subunits.
      2. The function of GABA_A receptors is modulated by a wide variety of pharmacologic agents, including convulsants, anticonvulsants, sedatives, anxiolytics, and anesthetics.
      3. Barbiturates, anesthetic steroids, benzodiazepines, propofol, etomidate, and the volatile anesthetics all modulate GABA_A receptor function (potentiation, direct gating, inhibition).
      4. Despite the similar effects of many anesthetics on GABA_A receptor function, different anesthetics act on distinct subtypes of GABA_A receptors (benzodiazepine sensitivity requires the presence of the γ2 subunit subtype; sensitivity to etomidate requires the presence of a β2 or β3 subunit).
   3. Other Ligand-Activated Ion Channels. Ligand-gated receptors structurally similar to the GABA_A receptor, including the nicotinic acetylcholine receptors (muscle and neuronal types), glycine receptors, and 5-HT₃ receptors, have been shown to be modulated by general anesthetics.
      1. Glycine is an important inhibitory neurotransmitter, particularly in the spinal cord and brainstem (volatile anesthetics potentiate glycine-activated currents). The glycine receptor is a member of the ligand-activated channel superfamily that, similar to the GABA_A receptor, is a chloride-selective ion channel.
      2. The 5-HT₃ receptors are also members of the genetically related super family of ligand-gated receptor channels (volatile anesthetics potentiate currents activated by 5-hydroxytryptamine). The 5-HT₃ receptors may play some role in the anesthetic state produced by volatile anesthetics and may also contribute to some unpleasant anesthetic side effects such as nausea and vomiting.

Mechanisms of Anesthesia and Consciousness

1. What is Anesthesia?
2. How is Anesthesia Measured?
3. What is the Chemical Nature of Anesthetic Target Sites?
4. How Do Anesthetics Interfere with the Electrophysiologic Function of the Nervous System?
5. Anesthetic Actions on Ion Channels
6. How are the Molecular Effects of Anesthetics Linked to Anesthesia in the Intact Organism?
7. Where in the Central Nervous System Do Anesthetics Work?
8. Conclusions