Functional sites involved in modulation of the GABAA receptor channel by the intravenous anesthetics propofol, etomidate and pentobarbital

Neuropharmacology
Maria C MaldifassiE Sigel

Abstract

GABAA receptors are the major inhibitory neurotransmitter receptors in the brain and are the target for many clinically important drugs. Among the many modulatory compounds are also the intravenous anesthetics propofol and etomidate, and barbiturates. The mechanism of receptor modulation by these compounds is of mayor relevance. The site of action of these compounds has been located to subunit interfaces in the intra-membrane region of the receptor. In α1β2γ2 GABAA receptors there are five such interfaces, two β+/α- and one each of α+/β-, α+/γ- and γ+/β- subunit interfaces. We have used reporter mutations located in the second trans-membrane region in different subunits to probe the effects of changes at these subunit interfaces on modulation by propofol, etomidate and pentobarbital. We provide evidence for the fact that each of these compounds either modulates through a different set of subunit interfaces or through the same set of subunit interfaces to a different degree. As a GABAA receptor pentamer harbors two β+/α- subunit interfaces, we used concatenated receptors to dissect the contribution of individual interfaces and show that only one of these interfaces is important for receptor modulation by etomidate.

References

Jan 1, 1994·Annual Review of Neuroscience·R L Macdonald, R W Olsen
May 1, 1995·Trends in Pharmacological Sciences·G B Smith, R W Olsen
May 10, 1994·Proceedings of the National Academy of Sciences of the United States of America·P B WingroveP J Whiting
Oct 6, 1997·Proceedings of the National Academy of Sciences of the United States of America·D BelelliP J Whiting
Jan 14, 1998·Trends in Pharmacological Sciences·E Sigel, A Buhr
Apr 3, 1999·The Journal of Biological Chemistry·S J FarrarR M McKernan
Jul 24, 2001·The Journal of Biological Chemistry·S W BaumannE Sigel
Sep 27, 2002·The Journal of Biological Chemistry·Sabine W BaumannErwin Sigel
Dec 12, 2002·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Rachel JurdUwe Rudolph
Jan 15, 2004·Molecular Pharmacology·Moez Bali, Myles H Akabas
May 12, 2004·Proceedings of the National Academy of Sciences of the United States of America·Frédéric Minier, Erwin Sigel
Feb 11, 2005·Molecular Nutrition & Food Research·Erwin Sigel, Frédéric Minier
Mar 2, 2005·Nature Reviews. Neuroscience·Mark Farrant, Zoltan Nusser
Jun 17, 2005·Nature Reviews. Neuroscience·Delia Belelli, Jeremy J Lambert
Nov 23, 2005·Journal of Neurochemistry·Nathalie BoulineauErwin Sigel
Nov 10, 2006·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Guo-Dong LiJonathan B Cohen
Jan 26, 2010·Trends in Pharmacological Sciences·Paul S Miller, Trevor G Smart
Sep 10, 2010·The Journal of Pharmacology and Experimental Therapeutics·Mandy L McCrackenR Adron Harris
Dec 30, 2010·Current Topics in Medicinal Chemistry·Erwin Sigel, Benjamin P Lüscher
Aug 3, 2011·British Journal of Pharmacology·Sebastian P FernandezJane R Hanrahan
Oct 6, 2012·The Journal of Biological Chemistry·Erwin Sigel, Michael E Steinmann
Sep 24, 2013·Nature Chemical Biology·Grace M S YipNicholas P Franks
Jun 25, 2014·ACS Chemical Biology·Simon J MiddendorpErwin Sigel

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Citations

May 21, 2016·Scientific Reports·Maria C MaldifassiErwin Sigel
Jul 6, 2016·Frontiers in Molecular Neuroscience·Roshan PuthenkalamMargot Ernst
Jun 21, 2016·Journal of Neurochemistry·Maria C MaldifassiErwin Sigel
Jun 29, 2017·Medicine·Jinfeng LiuHuacheng Zhou
Feb 23, 2019·Journal of Neural Engineering·Amirali ToossiVivian K Mushahwar
Jan 19, 2017·Oncotarget·Maria C Maldifassi, Erwin Sigel
Nov 9, 2016·The Journal of Biological Chemistry·David C ChiaraJonathan B Cohen
Mar 3, 2020·Neuropharmacology·Graeme J Sills, Michael A Rogawski
Feb 3, 2021·International Journal of Molecular Sciences·Vincenzo SorrentiStefano Vassanelli
Jan 3, 2018·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Hua-Jun Feng, Stuart A Forman
Jul 10, 2021·Translational Neuroscience·Caroline Lahogue, Didier Pinault
Aug 22, 2021·Journal, Genetic Engineering & Biotechnology·Amr GhitDiaa Eldin E Hussein

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