Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Pharmaceuticals (Basel)
2016 Feb 06;91:. doi: 10.3390/ph9010008.
Show Gene links
Show Anatomy links
Propofol and AZD3043 Inhibit Adult Muscle and Neuronal Nicotinic Acetylcholine Receptors Expressed in Xenopus Oocytes.
Jonsson Fagerlund M
,
Krupp J
,
Dabrowski MA
.
???displayArticle.abstract???
Propofol is a widely used general anaesthetic with muscle relaxant properties. Similarly as propofol, the new general anaesthetic AZD3043 targets the GABAA receptor for its anaesthetic effects, but the interaction with nicotinic acetylcholine receptors (nAChRs) has not been investigated. Notably, there is a gap of knowledge about the interaction between propofol and the nAChRs found in the adult neuromuscular junction. The objective was to evaluate whether propofol or AZD3043 interact with the α1β1δε, α3β2, or α7 nAChR subtypes that can be found in the neuromuscular junction and if there are any differences in affinity for those subtypes between propofol and AZD3043. Human nAChR subtypes α1β1δε, α3β2, and α7 were expressed into Xenopus oocytes and studied with an automated voltage-clamp. Propofol and AZD3043 inhibited ACh-induced currents in all of the nAChRs studied with inhibitory concentrations higher than those needed for general anaesthesia. AZD3043 was a more potent inhibitor at the adult muscle nAChR subtype compared to propofol. Propofol and AZD3043 inhibit nAChR subtypes that can be found in the adult NMJ in concentrations higher than needed for general anaesthesia. This finding needs to be evaluated in an in vitro nerve-muscle preparation and suggests one possible explanation for the muscle relaxant effect of propofol seen during higher doses.
Figure 1. Propofol and AZD3043 concentration-dependently inhibit 1 µM acetylcholine-induced current responses in Xenopus oocytes expressing the human muscle (α1β1δε) nAChR. Representative traces from one oocyte inhibited by propofol (Prop) respectively AZD3043 (A). Concentration-dependent inhibition of currents induced by 1 µM ACh by propofol and AZD3043 (B). Current responses in each oocyte were normalized to the 1 µM acetylcholine control responses in each oocyte as described in Materials and Methods. Each symbol represents mean ± S.E.M. When no error bars are seen, they are smaller than the symbols. Ach = acetylcholine, Prop = propofol.
Figure 2. Propofol and AZD3043 concentration-dependently inhibit 100 µM acetylcholine-induced current responses in Xenopus oocytes expressing the human neuronal α3β2 and α7 nAChR. Representative traces from one oocyte inhibited by propofol (Prop) or AZD3043 (A). Please note that the concentration-response curve for the human neuronal α7 nAChR subtype is based on area under the curve calculation and not peak (see Section 4.6.). Concentration-dependent inhibition of currents induced by 1 µM acetylcholine by propofol and AZD3043 at the human neuronal α3β2 and α7 nAChR subtypes (B). Current responses in each oocyte were normalized to the 100 µM acetylcholine control responses in each oocyte as described in Experimental Section. Each symbol represents mean ± S.E.M. When no error bars are seen, they are smaller than the symbols. Ach = acetylcholine, Prop = propofol.
Barker,
Movements of the vocal cords on induction of anaesthesia with thiopentone or propofol.
1992, Pubmed
Barker,
Movements of the vocal cords on induction of anaesthesia with thiopentone or propofol.
1992,
Pubmed
Dueck,
Propofol impairs the central but not the peripheral part of the motor system.
2003,
Pubmed
Eastwood,
Collapsibility of the upper airway at different concentrations of propofol anesthesia.
2005,
Pubmed
Eaton,
Differential effects of dimethyl sulfoxide on nicotinic acetylcholine receptors from mouse muscle and Torpedo electrocytes.
1997,
Pubmed
,
Xenbase
Egan,
AZD-3043: a novel, metabolically labile sedative-hypnotic agent with rapid and predictable emergence from hypnosis.
2012,
Pubmed
Fagerlund,
Current concepts in neuromuscular transmission.
2009,
Pubmed
Flood,
Alpha 4 beta 2 neuronal nicotinic acetylcholine receptors in the central nervous system are inhibited by isoflurane and propofol, but alpha 7-type nicotinic acetylcholine receptors are unaffected.
1997,
Pubmed
,
Xenbase
Franks,
General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal.
2008,
Pubmed
Furuya,
The effects of ketamine and propofol on neuronal nicotinic acetylcholine receptors and P2x purinoceptors in PC12 cells.
1999,
Pubmed
Ginz,
Effect of three anaesthetic techniques on isometric skeletal muscle strength.
2004,
Pubmed
Haeseler,
Propofol blocks human skeletal muscle sodium channels in a voltage-dependent manner.
2001,
Pubmed
Hurst,
Nicotinic acetylcholine receptors: from basic science to therapeutics.
2013,
Pubmed
Jayakar,
Identification of propofol binding sites in a nicotinic acetylcholine receptor with a photoreactive propofol analog.
2013,
Pubmed
Jonsson,
Distinct pharmacologic properties of neuromuscular blocking agents on human neuronal nicotinic acetylcholine receptors: a possible explanation for the train-of-four fade.
2006,
Pubmed
,
Xenbase
Jonsson,
Activation and inhibition of human muscular and neuronal nicotinic acetylcholine receptors by succinylcholine.
2006,
Pubmed
,
Xenbase
Jonsson Fagerlund,
Reduced efficacy of the intravenous anesthetic agent AZD3043 at GABA(A) receptors with β2 (N289M) and β3 (N290M) point-mutations.
2012,
Pubmed
,
Xenbase
Jonsson Fagerlund,
Pharmacological characteristics of the inhibition of nondepolarizing neuromuscular blocking agents at human adult muscle nicotinic acetylcholine receptor.
2009,
Pubmed
,
Xenbase
Jonsson Fagerlund,
Reduced effect of propofol at human {alpha}1{beta}2(N289M){gamma}2 and {alpha}2{beta}3(N290M){gamma}2 mutant GABA(A) receptors.
2010,
Pubmed
,
Xenbase
Lam,
Modulatory and direct effects of propofol on recombinant GABAA receptors expressed in xenopus oocytes: influence of alpha- and gamma2-subunits.
1998,
Pubmed
,
Xenbase
Martyn,
Succinylcholine-induced hyperkalemia in acquired pathologic states: etiologic factors and molecular mechanisms.
2006,
Pubmed
McKeating,
The effects of thiopentone and propofol on upper airway integrity.
1988,
Pubmed
Papke,
Comparative pharmacology of rat and human alpha7 nAChR conducted with net charge analysis.
2002,
Pubmed
,
Xenbase
Richardson,
A conserved tyrosine in the beta2 subunit M4 segment is a determinant of gamma-aminobutyric acid type A receptor sensitivity to propofol.
2007,
Pubmed
Rudolph,
Molecular and neuronal substrates for general anaesthetics.
2004,
Pubmed
Sieghart,
Structure, pharmacology, and function of GABAA receptor subtypes.
2006,
Pubmed
Smith,
The interaction of fentanyl on the Cp50 of propofol for loss of consciousness and skin incision.
1994,
Pubmed
Taha,
Propofol is superior to thiopental for intubation without muscle relaxants.
2005,
Pubmed
Violet,
Differential sensitivities of mammalian neuronal and muscle nicotinic acetylcholine receptors to general anesthetics.
1997,
Pubmed
,
Xenbase
