Inhibition of m3 muscarinic acetylcholine receptors by local anaesthetics

British Journal of Pharmacology
M W HollmannM E Durieux

Abstract

1. Muscarinic m1 receptors are inhibited by local anaesthetics (LA) at nM concentrations. To elucidate in more detail the site(s) of LA interaction, we compared these findings with LA effects on m3 muscarinic receptors. 2. We expressed receptors in Xenopus oocytes. Using two-electrode voltage clamp, we measured the effects of lidocaine, QX314 (permanently charged) and benzocaine (permanently uncharged) on Ca(2+)-activated Cl(-)-currents (I(Cl(Ca))), elicited by acetyl-beta-methylcholine bromide (MCh). We also characterized the interaction of lidocaine with [(3)H]-quinuclydinyl benzylate ([(3)H]-QNB) binding to m3 receptors. Antisense-injection was used to determine the role of specific G-protein alpha subunits in mediating the inhibitory effects of LA. Using chimeric receptor constructs we investigated which domains of the muscarinic receptors contribute to the binding site for LA. 3. Lidocaine inhibited m3-signalling in a concentration-dependent, reversible, non-competitive manner with an IC(50) of 370 nM, approximately 21 fold higher than the IC(50) (18 nM) reported for m1 receptors. Intracellular inhibition of both signalling pathways by LA was similar, and dependent on the G(q)- protein alpha subunit. In contrast to results...Continue Reading

References

Apr 1, 1989·Trends in Neurosciences·T I Bonner
Jan 1, 1989·International Anesthesiology Clinics·R S Aronstam, R L Dennison
Dec 15, 1995·The Journal of Biological Chemistry·L Stehno-BittelD E Clapham
Jul 25, 1998·The Journal of Biological Chemistry·H ShapiraJ F Battey
Jul 26, 2000·Anesthesiology·M W HollmannM E Durieux

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Citations

Apr 17, 2004·Der Anaesthesist·S PecherM W Hollmann
Oct 27, 2012·Journal of Anesthesia·Kouichiro Minami, Yasuhito Uezono
Jun 6, 2003·European Journal of Pharmacology·Motonari YunokiKunio Ishii
Sep 26, 2013·British Journal of Anaesthesia·S PicardiM W Hollmann
Apr 25, 2006·The Journal of Pain : Official Journal of the American Pain Society·Ron AmirGary R Strichartz
Dec 8, 2005·International Immunopharmacology·Sigrid WittmannStephen Daniels
Feb 17, 2015·Acta Anaesthesiologica Scandinavica·M J MakdessiG R Strichartz
Dec 3, 2002·Anesthesiology·Markus W HollmannMarcel E Durieux
Oct 25, 2003·Anesthesiology·Claudia BenkwitzMarkus W Hollmann
Apr 17, 2004·Anesthesiology·Markus W HollmannMarcel E Durieux
Aug 31, 2004·Anesthesia and Analgesia·Christian W HönemannMarcel E Durieux
Sep 14, 2019·Mini Reviews in Medicinal Chemistry·Syeda Khair-Ul-BariyahEjaz Ahmed
Nov 14, 2007·Expert Review of Neurotherapeutics·Theodore R Cummins, Anthony M Rush
Aug 14, 2002·British Journal of Anaesthesia·A Scholz
Sep 4, 2021·Molecular Pharmacology·Stephan L GrageStefan Weinschenk

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