Positive modulation of human GABAA and glycine receptors by the inhalation anesthetic isoflurane
Department of Pharmacological and Physiological Sciences, University of Chicago, Illinois 60637. Molecular Pharmacology
(Impact Factor: 4.13).
The interactions of the inhalation anesthetic agent isoflurane with ligand-gated chloride channels were studied using transient expression of recombinant human receptors in a mammalian cell line. Isoflurane enhanced gamma-aminobutyric acid (GABA)-activated chloride currents in cells that expressed heteromeric GABAA receptors consisting of combinations of alpha 1 or alpha 2, beta 1, and gamma 2 subunits and in cells that expressed receptors consisting of combinations of only alpha and beta subunits. Receptors consisting of alpha 2 and gamma 2 subunits were poorly expressed but were sensitive to isoflurane. Receptors consisting of beta 1 and gamma 2 subunits were not expressed. Isoflurane also enhanced glycine-activated chloride currents through homomeric alpha glycine receptors but did not enhance GABA currents in cells expressing homomeric rho 1 receptors. These results show that not all ligand-gated chloride channel receptors are sensitive to isoflurane and, therefore, that the anesthetic interacts with specific structural determinants of these ion channel proteins.
Available from: Veit-Simon Eckle
- "As they are both permeable to chloride ions, activation of these receptors causes inhibition of neuronal excitability in the central nervous system. Within the range of clinically relevant concentrations, volatile anesthetics potentiate the function of GABAA and glycine receptors , . Moreover, the molecular structure of the binding site of volatile anesthetics on GABAA and glycine receptors is quite similar . "
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ABSTRACT: Background: The ventral horn is a major substrate in mediating the immobilizing properties of the volatile anesthetic sevoflurane in the spinal cord. In this neuronal network, action potential firing is controlled by GABA(A) and glycine receptors. Both types of ion channels are sensitive to volatile anesthetics, but their role in mediating anesthetic-induced inhibition of spinal locomotor networks is not fully understood.
Methodology/Principal Findings: To compare the effects of sevoflurane on GABAergic and glycinergic inhibitory postsynaptic currents (IPSCs) whole-cell voltage-clamp recordings from ventral horn interneurons were carried out in organotypic spinal cultures. At concentrations close to MAC (minimum alveolar concentration), decay times of both types of IPSCs were significantly prolonged. However, at 1.5 MAC equivalents, GABAergic IPSCs were decreased in amplitude and reduced in frequency. These effects counteracted the prolongation of the decay time, thereby decreasing the timeaveraged GABAergic inhibition. In contrast, amplitudes and frequency of glycinergic IPSCs were not significantly altered by sevoflurane. Furthermore, selective GABA(A) and glycine receptor antagonists were tested for their potency to reverse sevoflurane-induced inhibition of spontaneous action potential firing in the ventral horn. These experiments confirmed a weak impact of GABA(A) receptors and a prominent role of glycine receptors at a high sevoflurane concentration.
Conclusions: At high concentrations, sevoflurane mediates neuronal inhibition in the spinal ventral horn primarily via glycine receptors, and less via GABA(A) receptors. Our results support the hypothesis that the impact of GABA(A) receptors in mediating the immobilizing properties of volatile anesthetics is less essential in comparison to glycine receptors.
Available from: Hanns Ulrich Zeilhofer
- "Many studies on recombinant GlyRs consistently demonstrate that volatile anaesthetics, such as isoflurane, enflurane, halothane and sevoflurane potentiate homomeric α1-GlyR currents at anaesthetic concentrations (Downie et al., 1996; Krasowski and Harrison, 1999; Mascia et al., 1996a; Yamakura et al., 2001). This potentiation is not specific for α1-GlyRs, as homomeric α2-GlyRs are also sensitive to isoflurane (Harrison et al., 1993), while "
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ABSTRACT: Inhibitory (or strychnine sensitive) glycine receptors (GlyRs) are anion-selective transmitter-gated ion channels of the cys-loop superfamily, which includes among others also the inhibitory -aminobutyric acid receptors (GABAA receptors). While GABA mediates fast inhibitory neurotransmission throughout the CNS, the action of glycine as a fast inhibitory neurotransmitter is more restricted. This probably explains why GABAA receptors constitute a group of extremely successful drug targets in the treatment of a wide variety of CNS diseases, including anxiety, sleep disorders and epilepsy, while drugs specifically targeting GlyRs are virtually lacking. However, the spatially more restricted distribution of glycinergic inhibition may be advantageous in situations when a more localized enhancement of inhibition is sought. Inhibitory GlyRs are particularly relevant for the control of excitability in the mammalian spinal cord, brain stem and a few selected brain areas, such as the cerebellum and the retina. At these sites, GlyRs regulate important physiological functions, including respiratory rhythms, motor control, muscle tone and sensory as well as pain processing. In the hippocampus, RNA-edited high affinity extrasynaptic GlyRs may contribute to the pathology of temporal lobe epilepsy. Although specific modulators have not yet been identified, GlyRs still possess sites for allosteric modulation by a number of structurally diverse molecules, including alcohols, neurosteroids, cannabinoids, tropeines, general anaesthetics, certain neurotransmitters and cations. This review summarizes the present knowledge about this modulation and the molecular bases of the interactions involved.
Available from: Lemont B Kier
- "This interference with chreodes leads to a reduction in their function, which is to facilitate and direct transmitter molecule diffusion to its receptor. The variety of these receptor types influenced, and the modest degree of the interference, is compatible with the current understanding of general anesthetic mechanisms [19, 26]. The inspired volatile anesthetic agent diffuses through a large part of the body, encountering several neurotransmitter systems. "
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ABSTRACT: The concept of the presence of passageways, chreodes, created by the influence of the hydropathic states of amino acid side chains on the surface water of proteins, has been proposed. These chreodes facilitate and direct the diffusion of neurotransmitters through surface water, to the receptor or active site on a protein. This system of chreodes is vulnerable to the presence of some other molecules that may encounter the chreode system. This encounter and disruption has been proposed to explain the mechanism of general anesthesia. Based on much recent evidence of the similarities between anesthesia from volatile anesthetic agents and sleep, a comparable mechanism has been proposed for sleep. Since this must be an exogenous substance to be comparable to a general anesthetic agent, it was proposed that this exogenous, sleep-producing substance is elemental nitrogen. Recent evidence supports these hypotheses.
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