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ANESTHETIC PHARMACOLOGY

A Transmembrane Residue Influences the Interaction of Propofol with the Strychnine-Sensitive Glycine ₁ and ₁β Receptor

Jörg Ahrens, MD^*, Martin Leuwer, MD, Sina Stachura, MD^*, Klaus Krampfl, MD, Delia Belelli, MD, Jeremy J. Lambert, MD, and Gertrud Haeseler, MD^*

From the *Department of Anesthesiology, Hannover Medical School, Hannover, Germany; Division of Clinical Sciences, The University of Liverpool, Liverpool, UK; Department of Neurology and Neurophysiology, Hannover Medical School, Hannover, Germany; and Neurosciences Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.

Address correspondence and reprint requests to Jörg Ahrens, MD, Department of Anesthesiology, OE 8050, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Address e-mail to ahrens.j{at}mh-hannover.de.

BACKGROUND: Propofol, well known for its anesthetic effects, acts as a positive allosteric modulator of the -aminobutyric acid type A (GABA_A) receptor but also enhances the function of the glycine receptor. The GABA modulatory effects of propofol are influenced by an amino acid residue located within the second transmembrane domain (TM2) of the GABA_A receptor β subunit. In glycine ₁ subunits, the homologous residue (serine 267) affects the glycine modulatory actions of alcohols and alkane anesthetics. In the present study we investigated the role of this residue on the interaction of propofol with the glycine ₁ and ₁β receptor.

METHODS: The influence of propofol on wild type and mutant (₁S267M, ₁S267I, ₁S267Mβ, ₁S267Iβ) glycine receptors expressed in human embryonic kidney 293 cells was investigated by using the whole-cell clamp technique.

RESULTS: Mutation of the ₁ subunit TM2 serine residue to either isoleucine or methionine decreased the sensitivity of the receptor to glycine, and abolished the direct activation of the glycine receptor by propofol. Additionally, the methionine and particularly the isoleucine mutation decreased the glycine-enhancing actions of propofol.

CONCLUSIONS: The nature of the TM2 residue (267) of the glycine ₁ subunit influences the glycine modulatory effect of propofol and direct activation of the receptor by this anesthetic. A comparison of the impact of such complementary mutations on the interaction of propofol with glycine and GABA_A receptors should permit a better understanding of the molecular determinants of action of propofol on these structurally related receptors and may aid in the development of selective glycine receptor modulators.

Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999