title: 4-Chloropropofol enhances chloride currents in human hyperekplexic and artificial mutated glycine receptors.
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.
authors.affiliation: Clinic for Anesthesia and Critical Care Medicine, OE 8050, Hannover Medical School, Carl-Neuberg-Str, 1, 30625, Hannover, Germany. delaroche.jeanne@mh-hannover.de
authors.forename: Jeanne
authors.initials: J
authors.lastname: de la Roche
authors.forename: Martin
authors.initials: M
authors.lastname: Leuwer
authors.forename: Klaus
authors.initials: K
authors.lastname: Krampfl
authors.forename: Gertrud
authors.initials: G
authors.lastname: Haeseler
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dengler
authors.forename: Vanessa
authors.initials: V
authors.lastname: Buchholz
authors.forename: Jörg
authors.initials: J
authors.lastname: Ahrens
mesh_terms: D002713:Chlorine / Q000378:metabolism*; D002733:Chlorophenols / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000378:metabolism*; D040181:Genetic Diseases, X-Linked / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects*; D016297:Mutagenesis, Site-Directed; D018009:Receptors, Glycine / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D012021:Reflex, Abnormal; D014992:Xylenes
chemical_list: D002733:Chlorophenols; D018009:Receptors, Glycine; D014992:Xylenes; C007027:chloroxylenol; D002713:Chlorine