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Open Access Research article

4-Chloropropofol enhances chloride currents in human hyperekplexic and artificial mutated glycine receptors

Jeanne de la Roche1*, Martin Leuwer2, Klaus Krampfl3, Gertrud Haeseler4, Reinhard Dengler3, Vanessa Buchholz1 and Jörg Ahrens1

Author Affiliations

1 Clinic for Anesthesia and Critical Care Medicine, OE 8050, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

2 Critical Care Research Unit, The University of Liverpool, Daulby Street, Liverpool, L69 3, GA, U.K

3 Department of Neurology and Neurophysiology; OE 7210, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

4 Clinic for Anesthesia and Critical Care Medicine, St. Elisabeth-Hospital Dorsten, Pfarrer-Wilhelm-Schmitz Str., 1 46282, Dorsten, Germany

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BMC Neurology 2012, 12:104  doi:10.1186/1471-2377-12-104

Published: 24 September 2012

Abstract

Background

The mammalian neurological disorder hereditary hyperekplexia can be attributed to various mutations of strychnine sensitive glycine receptors. The clinical symptoms of “startle disease” predominantly occur in the newborn leading to convulsive hypertonia and an exaggerated startle response to unexpected mild stimuli. Amongst others, point mutations R271Q and R271L in the α1-subunit of strychnine sensitive glycine receptors show reduced glycine sensitivity and cause the clinical symptoms of hyperekplexia.

Halogenation has been shown to be a crucial structural determinant for the potency of a phenolic compound to positively modulate glycine receptor function.

The aim of this in vitro study was to characterize the effects of 4-chloropropofol (4-chloro-2,6-dimethylphenol) at four glycine receptor mutations.

Methods

Glycine receptor subunits were expressed in HEK 293 cells and experiments were performed using the whole-cell patch-clamp technique.

Results

4-chloropropofol exerted a positive allosteric modulatory effect in a low sub-nanomolar concentration range at the wild type receptor (EC50 value of 0.08 ± 0.02 nM) and in a micromolar concentration range at the mutations (1.3 ± 0.6 μM, 0.1 ± 0.2 μM, 6.0 ± 2.3 μM and 55 ± 28 μM for R271Q, L, K and S267I, respectively).

Conclusions

4-chloropropofol might be an effective compound for the activation of mutated glycine receptors in experimental models of startle disease.

Keywords:
Glycine receptor mutations; Hereditary hyperekplexia; 4-chloropropofol