Abbildungen
Abb. 1 Struktur des Glycin-Rezeptors (30) 8
Abb. 2 Startle Mutationen am humanen 1-GlyR (85) 11
Abb. 3 Strukturformel von Propofol 17 Abb. 4 Strukturformeln der in para-Position substituierten Propofolderivate 23 Abb. 5 Substituiertes Propofol in para-Position 24 Abb. 6 Schaltbild eines Patch-Clamp-Verstärkers und Ersatzschaltbild der Ganzzellableitung (216) 36 Abb. 7 Die Patch-Clamp-Konfigurationen (1) 37 Abb. 8 Patch-Clamp-Messstand 38
Abb. 9 Die Messkammer 39
Abb. 10 Anpatchen einer fluoreszierenden Zelle 40 Abb. 11 Positionieren der Pipettenspitze mit Zelle im Messstrahl 41 Abb. 12 Repräsentative Stromspuren für die Aktivierung durch Glycin am α1-GlyR 46 Abb. 13 Konzentrations-Wirkungskurve für die Aktivierung von α -GlyR (WT) durch den natürlichen
Agonisten Glycin
1
46 Abb. 14 Repräsentative Stromspuren für die Aktivierung durch Glycin am α1S267I-GlyR 47 Abb. 15 Konzentrations-Wirkungskurve für die Aktivierung von α S267I-GlyR durch den natürlichen
Agonisten Glycin
1
48 Abb. 16 Repräsentative Stromspuren zur Aktivierung durch Glycin am α1R271Q-GlyR 49 Abb. 17 Konzentrations-Wirkungskurve für die Aktivierung von α R271Q-GlyR durch den natürlichen
Agonisten Glycin
1
49 Abb. 18 Repräsentative Stromspuren zur Aktivierung durch Glycin am α1R271L-GlyR 50 Abb. 19 Konzentrations-Wirkungskurve für die Aktivierung von α R271L-GlyR durch den natürlichen
Agonisten Glycin
1
51 Abb. 20 4-Chlorpropofol Abb. 21 4-Iodpropofol Abb. 22 4-Brompropofol 53 Abb. 23 Repräsentative Stromspuren zur Co-Aktivierung von 4-Chlorpropofol am α1-GlyR 54 Abb. 24 Konzentrations-Wirkungskurve für die Coaktivierung von 4-Chlorpropofol am α1-GlyR 54 Abb. 25 Repräsentative Stromspuren zur Co-Aktivierung von 4-Iodpropofol am α1-GlyR 55 Abb. 26 Konzentrations-Wirkungskurve für die Coaktivierung von 4-Iodpropofol am α1-GlyR 56 Abb. 27 Repräsentative Stromspuren zur Co-Aktivierung von 4-Brompropofol am α1-GlyR 57 Abb. 28 Konzentrations-Wirkungskurve für die Co-Aktivierung von 4-Brompropofol am 1-GlyR 57 Abb. 29 Repräsentative Stromspuren zur Co-Aktivierung von 4-Chlorpropofol am α1R271Q-GlyR 60 Abb. 30 Konzentrations-Wirkungskurve zur Co-Aktivierung von 4-Chlorpropofol am α1R271Q-GlyR 60 Abb. 31 Repräsentative Stromspuren zur Direkt-Aktivierung von 4-Chlorpropofol am α1R271Q-GlyR 61 Abb. 32 Repräsentative Stromspuren zur Co-Aktivierung von 4-Chlorpropofol am α1R271L-GlyR 63 Abb. 33 Konzentrations-Wirkungskurve zur Co-Aktivierung von 4-Chlorpropofol am α1R271L-GlyR 63 Abb. 34 Repräsentative Stromspuren zur Direkt-Aktivierung von 4-Chlorpropofol am α1R271L-GlyR 64 Abb. 35 Repräsentative Stromspuren zur Direkt-Aktivierung von 4-Chlorpropofol am α1S267M-GlyR 66 Abb. 36 Repräsentative Stromspuren zur Direkt-Aktivierung von 4-Iodpropofol am α1S267M-GlyR 67 Abb. 37 Repräsentative Stromspuren zur Direkt-Aktivierung von 4-Brompropofol am α1S267M-GlyR 68 Abb. 38 Repräsentative Strompspuren zur Co-Aktivierung von 4-Chlorpropofol am α1S267I-GlyR 70 Abb. 39 Konzentrations-Wirkungskurve zur Co-Aktivierung von 4-Chlorpropofol am 1S267I-GlyR 71 Abb. 40 Repräsentative Stromspuren zur Direkt-Aktivierung von 4-Chlorpropofol am α1S267I-GlyR 72 Abb. 41 Repräsentative Stromspuren zur Co-Aktivierung von 4-Iodpropofol am α1S267I-GlyR 73 Abb. 42 Konzentrations-Wirkungskurve zur Co-Aktivierung von 4-Iodpropofol am 1S267I-GlyR 73 Abb. 43 Repräsentative Stromspuren zur Direkt-Aktivierung von 4-Iodpropofol am α1S267I-GlyR 74 Abb. 44 Repräsentative Stromspuren zur Co-Aktivierung von 4-Brompropofol am α1S267I-GlyR 75 Abb. 45 Konzentrations-Wirkungskurve zur Co-Aktivierung von 4-Brompropofol am α1S267I-GlyR 76 Abb. 46 Repräsentative Stromspuren zur Direkt-Aktivierung von 4-Brompropofol am α1S267I-GlyR 77
Tabellen
Tabelle 1 LB-Agar und Antibiotikazusätze 27 Tabelle 2 LB-Flüssigmedien und Antibiotikazusätze 28 Tabelle 3 Pharmakologische Eigenschaften von Glycin an den untersuchten Rezeptoren 52 Tabelle 4 Pharmakologische Eigenschaften von 4-Chlor-, 4-Iod-, 4-Brompropofol am α1-GlyR 58 Tabelle 5 Pharmakologische Eigenschaften von 4-Chlorpropofol am α1R271Q-GlyR 62 Tabelle 6 Pharmakologische Eigenschaften von 4-Chlorpropofol am α1R271L-GlyR 65 Tabelle 7 Pharmakologische Eigenschaften von 4-Chlor-, 4-Iod-, 4-Brompropofol am α1S267M-GlyR
69 Tabelle 8 Pharmakologische Eigenschaften von 4-Chlor-, 4-Iod-, 4-Brompropofol am α1S267I-GlyR 78
7 Literaturangaben
(1) Hammond C. Cellular and Molecular Neurobiology. 2nd ed. Marseille, France: Academic Press, 2001.
(2) Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson JD. Molecular Biology of the Cell. Book 1989; 2nd:693-695.
(3) Schmidt RF TG, Lang F. Physiologie des Menschens. Book 2005; 29.
(4) Hille B. Ion channels of excitable membranes. Book 1992; 2nd.
(5) Servent D, Fruchart-Gaillard C. Muscarinic toxins: tools for the study of the pharmacological and functional properties of muscarinic receptors. J
Neurochem 2009; 109(5):1193-1202.
(6) Ma MC, Huang HS, Chen YS, Lee SH. Mechanosensitive N-methyl-D-aspartate receptors contribute to sensory activation in the rat renal pelvis.
Hypertension 2008; 52(5):938-944.
(7) Rong Y, Lu X, Bernard A, Khrestchatisky M, Baudry M. Tyrosine
phosphorylation of ionotropic glutamate receptors by Fyn or Src differentially modulates their susceptibility to calpain and enhances their binding to
spectrin and PSD-95. J Neurochem 2001; 79(2):382-390.
(8) Gutman GA, Chandy KG, Grissmer S, Lazdunski M, McKinnon D, Pardo LA et al. International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels. Pharmacol Rev 2005;
57(4):473-508.
(9) Yu FH, Catterall WA. Overview of the voltage-gated sodium channel family.
Genome Biol 2003; 4(3):207.
(10) Dolphin AC. A short history of voltage-gated calcium channels. Br J Pharmacol 2006; 147 Suppl 1:S56-62.:S56-S62.
(11) Morgan D, DeCoursey TE. Diversity of voltage gated proton channels. Front Biosci 2003; 8:s1266-79.:s1266-s1279.
(12) Dudel J. Neuro-und Sinnesphysiologie (Schmidt RF, Schaible H-G). Book 2006; 5.Auflage(Springer-Verlag).
(13) Campbell NA. Biologie. Book 1998;1096-1097.
(14) Connolly CN, Wafford KA. The Cys-loop superfamily of ligand-gated ion channels: the impact of receptor structure on function. Biochem Soc Trans 2004; 32(Pt3):529-534.
(15) Dingledine R, Borges K, Bowie D, Traynelis SF. The glutamate receptor ion channels. Pharmacol Rev 1999; 51(1):7-61.
(16) Roberts JA, Vial C, Digby HR, Agboh KC, Wen H, Atterbury-Thomas A et al.
Molecular properties of P2X receptors. Pflugers Arch 2006; 452(5):486-500.
(17) Ramsey IS, Delling M, Clapham DE. An introduction to TRP channels. Annu Rev Physiol 2006; 68:619-47.:619-647.
(18) Brejc K, van Dijk WJ, Klaassen RV, Schuurmans M, van Der OJ, Smit AB et al. Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature 2001; 411(6835):269-276.
(19) Betz H. Ligand-gated ion channels in the brain: the amino acid receptor superfamily. Neuron 1990; 5(4):383-392.
(20) Jensen ML, Schousboe A, Ahring PK. Charge selectivity of the Cys-loop family of ligand-gated ion channels. J Neurochem 2005; 92(2):217-225.
(21) Unwin N. Neurotransmitter action: opening of ligand-gated ion channels. Cell 1993; 72 Suppl:31-41.:31-41.
(22) Absalom NL, Schofield PR, Lewis TM. Pore structure of the Cys-loop ligand-gated ion channels. Neurochem Res 2009; 34(10):1805-1815.
(23) Laube B, Maksay G, Schemm R, Betz H. Modulation of glycine receptor function: a novel approach for therapeutic intervention at inhibitory synapses? Trends Pharmacol Sci 2002; 23(11):519-527.
(24) Betz H, Laube B. Glycine receptors: recent insights into their structural organization and functional diversity. Journal of Neurochemistry 2006;
97(6):1600-1610.
(25) Langosch D, Becker CM, Betz H. The inhibitory glycine receptor: a ligand-gated chloride channel of the central nervous system. Eur J Biochem 1990;
194(1):1-8.
(26) Malosio ML, Marqueze-Pouey B, Kuhse J, Betz H. Widespread expression of glycine receptor subunit mRNAs in the adult and developing rat brain.
EMBO J 1991; 10(9):2401-2409.
(27) Lynch JW. Molecular structure and function of the glycine receptor chloride channel. Physiol Rev 2004; 84(4):1051-1095.
(28) Wassle H, Koulen P, Brandstatter JH, Fletcher EL, Becker CM. Glycine and GABA receptors in the mammalian retina. Vision Res 1998; 38(10):1411-1430.
(29) Betz H, Kuhse J, Schmieden V, Laube B, Kirsch J, Harvey RJ. Structure and functions of inhibitory and excitatory glycine receptors. Ann N Y Acad Sci 1999; 868:667-676.
(30) Legendre P. The glycinergic inhibitory synapse. Cell Mol Life Sci 2001; 58(5-6):760-793.
(31) Werman R, Davidoff RA, Aprison MH. Inhibition of motoneurones by iontophoresis of glycine. Nature 1967; 214(5089):681-683.
(32) Harvey RJ, Depner UB, Wassle H, Ahmadi S, Heindl C, Reinold H et al.
GlyR alpha3: an essential target for spinal PGE2-mediated inflammatory pain sensitization. Science 2004; 304(5672):884-887.
(33) Zeilhofer HU. The glycinergic control of spinal pain processing. Cell Mol Life Sci 2005; 62(18):2027-2035.
(34) Probst A, Cortes R, Palacios JM. The distribution of glycine receptors in the human brain. A light microscopic autoradiographic study using
[3H]strychnine. Neuroscience 1986; 17(1):11-35.
(35) Kuhse J, Betz H, Kirsch J. The inhibitory glycine receptor: architecture, synaptic localization and molecular pathology of a postsynaptic ion-channel complex. Curr Opin Neurobiol 1995; 5(3):318-323.
(36) Schmitt B, Knaus P, Becker CM, Betz H. The Mr 93,000 polypeptide of the postsynaptic glycine receptor complex is a peripheral membrane protein.
Biochemistry 1987; 26(3):805-811.
(37) Becker CM, Hoch W, Betz H. Glycine receptor heterogeneity in rat spinal cord during postnatal development. EMBO J 1988; 7(12):3717-3726.
(38) Takahashi T, Momiyama A, Hirai K, Hishinuma F, Akagi H. Functional correlation of fetal and adult forms of glycine receptors with developmental changes in inhibitory synaptic receptor channels. Neuron 1992; 9(6):1155-1161.
(39) Griffon N, Buttner C, Nicke A, Kuhse J, Schmalzing G, Betz H. Molecular determinants of glycine receptor subunit assembly. EMBO J 1999;
18(17):4711-4721.
(40) Sontheimer H, Becker CM, Pritchett DB, Schofield PR, Grenningloh G, Kettenmann H et al. Functional chloride channels by mammalian cell expression of rat glycine receptor subunit. Neuron 1989; 2(5):1491-1497.
(41) Grenningloh G, Schmieden V, Schofield PR, Seeburg PH, Siddique T, Mohandas TK et al. Alpha subunit variants of the human glycine receptor:
primary structures, functional expression and chromosomal localization of the corresponding genes. EMBO J 1990; 9(3):771-776.
(42) Schmieden V, Grenningloh G, Schofield PR, Betz H. Functional expression in Xenopus oocytes of the strychnine binding 48 kd subunit of the glycine receptor. EMBO J 1989; 8(3):695-700.
(43) Grudzinska J, Schemm R, Haeger S, Nicke A, Schmalzing G, Betz H et al.
The beta subunit determines the ligand binding properties of synaptic glycine receptors. Neuron 2005; 45(5):727-739.
(44) Ahrens J, Haeseler G, Leuwer M, Mohammadi B, Krampfl K, Dengler R et al.
2,6 di-tert-butylphenol, a nonanesthetic propofol analog, modulates alpha1beta glycine receptor function in a manner distinct from propofol.
Anesth Analg 2004; 99(1):91-96.
(45) Haeseler G, Ahrens J, Krampfl K, Bufler J, Dengler R, Hecker H et al.
Structural features of phenol derivatives determining potency for activation of chloride currents via alpha(1) homomeric and alpha(1)beta heteromeric glycine receptors. Br J Pharmacol 2005; 145(7):916-925.
(46) Langosch D, Thomas L, Betz H. Conserved quaternary structure of ligand-gated ion channels: the postsynaptic glycine receptor is a pentamer. Proc Natl Acad Sci U S A 1988; 85(19):7394-7398.
(47) Burzomato V, Groot-Kormelink PJ, Sivilotti LG, Beato M. Stoichiometry of recombinant heteromeric glycine receptors revealed by a pore-lining region point mutation. Receptors Channels 2003; 9(6):353-361.
(48) Vandenberg RJ, French CR, Barry PH, Shine J, Schofield PR. Antagonism of ligand-gated ion channel receptors: two domains of the glycine receptor alpha subunit form the strychnine-binding site. Proc Natl Acad Sci U S A 1992; 89(5):1765-1769.
(49) Arias HR. Localization of agonist and competitive antagonist binding sites on nicotinic acetylcholine receptors. Neurochem Int 2000; 36(7):595-645.
(50) Prior P, Schmitt B, Grenningloh G, Pribilla I, Multhaup G, Beyreuther K et al.
Primary structure and alternative splice variants of gephyrin, a putative glycine receptor-tubulin linker protein. Neuron 1992; 8(6):1161-1170.
(51) Kirsch J, Langosch D, Prior P, Littauer UZ, Schmitt B, Betz H. The 93-kDa glycine receptor-associated protein binds to tubulin. J Biol Chem 1991;
266(33):22242-22245.
(52) Meyer G, Kirsch J, Betz H, Langosch D. Identification of a gephyrin binding motif on the glycine receptor beta subunit. Neuron 1995; 15(3):563-572.
(53) Bormann J, Hamill OP, Sakmann B. Mechanism of anion permeation through channels gated by glycine and gamma-aminobutyric acid in mouse cultured spinal neurones. J Physiol 1987; 385:243-286.
(54) Keramidas A, Moorhouse AJ, Schofield PR, Barry PH. Ligand-gated ion channels: mechanisms underlying ion selectivity. Prog Biophys Mol Biol 2004; 86(2):161-204.
(55) Changeux JP, Edelstein SJ. Allosteric receptors after 30 years. Neuron 1998; 21(5):959-980.
(56) Breitinger HG. Fast kinetic analysis of ligand-gated ion channels.
Neuroscientist 2001; 7(2):95-103.
(57) Kuhse J, Laube B, Magalei D, Betz H. Assembly of the inhibitory glycine receptor: identification of amino acid sequence motifs governing subunit stoichiometry. Neuron 1993; 11(6):1049-1056.
(58) Mohammadi B, Krampfl K, Cetinkaya C, Moschref H, Grosskreutz J, Dengler R et al. Kinetic analysis of recombinant mammalian alpha(1) and
alpha(1)beta glycine receptor channels. Eur Biophys J 2003; 32(6):529-536.
(59) Dudel J. Erregungsbildung und -leitung im Nervensystem - Neurowissenschaft. Book, Springer-Verlag 2001; 2.Auflage.
(60) Harvey RJ, Topf M, Harvey K, Rees MI. The genetics of hyperekplexia: more than startle! Trends Genet 2008; 24(9):439-447.
(61) Planells-Cases R, Jentsch TJ. Chloride channelopathies. Biochim Biophys Acta 2009; 1792(3):173-189.
(62) Shiang R, Ryan SG, Zhu YZ, Hahn AF, O'Connell P, Wasmuth JJ. Mutations in the alpha 1 subunit of the inhibitory glycine receptor cause the dominant neurologic disorder, hyperekplexia. Nat Genet 1993; 5(4):351-358.
(63) Shiang R, Ryan SG, Zhu YZ, Fielder TJ, Allen RJ, Fryer A et al. Mutational analysis of familial and sporadic hyperekplexia. Ann Neurol 1995; 38(1):85-91.
(64) Rees MI, Lewis TM, Vafa B, Ferrie C, Corry P, Muntoni F et al. Compound heterozygosity and nonsense mutations in the alpha(1)-subunit of the inhibitory glycine receptor in hyperekplexia. Hum Genet 2001; 109(3):267-270.
(65) Becker K, Hohoff C, Schmitt B, Christen HJ, Neubauer BA, Sandrieser T et al. Identification of the microdeletion breakpoint in a GLRA1null allele of Turkish hyperekplexia patients. Hum Mutat 2006; 27(10):1061-1062.
(66) Siren A, Legros B, Chahine L, Misson JP, Pandolfo M. Hyperekplexia in Kurdish families: a possible GLRA1 founder mutation. Neurology 2006;
67(1):137-139.
(67) Kok O, Bruyn GW. An unidentified hereditary disease. The Lancet 1962.
(68) Floeter MK, Hallett M. Glycine Receptors - A Startling Connection. Nature Genetics 1993; 5(4):319-320.
(69) Andermann F, Keene DL, Andermann E, Quesney LF. Startle disease or hyperekplexia: further delineation of the syndrome. Brain 1980; 103(4):985-997.
(70) Stewart WA, Wood EP, Gordon KE, Camfield PR. Successful treatment of severe infantile hyperekplexia with low-dose clobazam. J Child Neurol 2002;
17(2):154-156.
(71) Andrew M, Owen MJ. Hyperekplexia: abnormal startle response due to glycine receptor mutations. Br J Psychiatry 1997; 170:106-108.
(72) Nowotny T, Rautenstrauch T, Vetter V. The jumpy girl. Case report on congenital hyperekplexia. Monatsschr Kinderheilkd, Springer Verlag 2001 2001; 12-2001(149):1366-1369.
(73) Praveen V, Patole SK, Whitehall JS. Hyperekplexia in neonates. Postgrad Med J 2001; 77(911):570-572.
(74) Kimura M, Taketani T, Horie A, Isumi H, Sejima H, Yamaguchi S. Two Japanese families with hyperekplexia who have a Arg271Gln mutation in the glycine receptor alpha 1 subunit gene. Brain Dev 2006; 28(4):228-231.
(75) Meinck HM. Startle and its disorders. Neurophysiol Clin 2006; 36(5-6):357-364.
(76) Garg R, Ramachandran R, Sharma P. Anaesthetic implications of
hyperekplexia--'startle disease'. Anaesth Intensive Care 2008; 36(2):254-256.
(77) Gastaut H, Villeneuve A. The startle disease or hyperekplexia. Pathological surprise reaction. J Neurol Sci 1967; 5(3):523-542.
(78) Zhou L, Chillag KL, Nigro MA. Hyperekplexia: a treatable neurogenetic disease. Brain Dev 2002; 24(7):669-674.
(79) Dooley JM, Andermann F. Startle Disease Or Hyperekplexia - Adolescent Onset and Response to Valproate. Pediatric Neurology 1989; 5(2):126-127.
(80) Rajendra S, Lynch JW, Pierce KD, French CR, Barry PH, Schofield PR.
Startle disease mutations reduce the agonist sensitivity of the human inhibitory glycine receptor. J Biol Chem 1994; 269(29):18739-18742.
(81) Langosch D, Laube B, Rundstrom N, Schmieden V, Bormann J, Betz H.
Decreased agonist affinity and chloride conductance of mutant glycine receptors associated with human hereditary hyperekplexia. EMBO J 1994;
13(18):4223-4228.
(82) Schorderet DF, Pescia G, Bernasconi A, Regli F. An additional family with Startle disease and a G1192A mutation at the alpha 1 subunit of the inhibitory glycine receptor gene. Hum Mol Genet 1994; 3(7):1201.
(83) Rees MI, Andrew M, Jawad S, Owen MJ. Evidence for recessive as well as dominant forms of startle disease (hyperekplexia) caused by mutations in the alpha 1 subunit of the inhibitory glycine receptor. Hum Mol Genet 1994;
3(12):2175-2179.
(84) Tijssen MA, Shiang R, van Deutekom J, Boerman RH, Wasmuth JJ,
Sandkuijl LA et al. Molecular genetic reevaluation of the Dutch hyperekplexia family. Arch Neurol 1995; 52(6):578-582.
(85) Elmslie FV, Hutchings SM, Spencer V, Curtis A, Covanis T, Gardiner RM et al. Analysis of GLRA1 in hereditary and sporadic hyperekplexia: a novel mutation in a family cosegregating for hyperekplexia and spastic
paraparesis. J Med Genet 1996; 33(5):435-436.
(86) Lynch JW, Rajendra S, Pierce KD, Handford CA, Barry PH, Schofield PR.
Identification of intracellular and extracellular domains mediating signal transduction in the inhibitory glycine receptor chloride channel. EMBO J 1997; 16(1):110-120.
(87) Bakker MJ, van Dijk JG, van den Maagdenberg AM, Tijssen MA. Startle syndromes. Lancet Neurol 2006; 5(6):513-524.
(88) O'Shea SM, Becker L, Weiher H, Betz H, Laube B. Propofol restores the function of "hyperekplexic" mutant glycine receptors in Xenopus oocytes and mice. J Neurosci 2004; 24(9):2322-2327.
(89) Langosch D, Laube B, Rundstrom N, Schmieden V, Bormann J, Betz H.
Decreased agonist affinity and chloride conductance of mutant glycine receptors associated with human hereditary hyperekplexia. EMBO J 1994;
13(18):4223-4228.
(90) Rajendra S, Lynch JW, Pierce KD, French CR, Barry PH, Schofield PR.
Startle disease mutations reduce the agonist sensitivity of the human inhibitory glycine receptor. J Biol Chem 1994; 269(29):18739-18742.
(91) Rees MI, Lewis TM, Kwok JB, Mortier GR, Govaert P, Snell RG et al.
Hyperekplexia associated with compound heterozygote mutations in the beta-subunit of the human inhibitory glycine receptor (GLRB). Hum Mol Genet 2002; 11(7):853-860.
(92) Rees MI, Harvey K, Pearce BR, Chung SK, Duguid IC, Thomas P et al.
Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease. Nat Genet 2006; 38(7):801-806.
(93) Eulenburg V, Becker K, Gomeza J, Schmitt B, Becker CM, Betz H. Mutations within the human GLYT2 (SLC6A5) gene associated with hyperekplexia.
Biochem Biophys Res Commun 2006; 348(2):400-405.
(94) Rees MI, Harvey K, Ward H, White JH, Evans L, Duguid IC et al. Isoform heterogeneity of the human gephyrin gene (GPHN), binding domains to the glycine receptor, and mutation analysis in hyperekplexia. J Biol Chem 2003;
278(27):24688-24696.
(95) Graham BA, Schofield PR, Sah P, Margrie TW, Callister RJ. Distinct
physiological mechanisms underlie altered glycinergic synaptic transmission in the murine mutants spastic, spasmodic, and oscillator. J Neurosci 2006;
26(18):4880-4890.
(96) Kling C, Koch M, Saul B, Becker CM. The frameshift mutation oscillator (Glra1(spd-ot)) produces a complete loss of glycine receptor
alpha1-polypeptide in mouse central nervous system. Neuroscience 1997;
78(2):411-417.
(97) Buckwalter MS, Cook SA, Davisson MT, White WF, Camper SA. A frameshift mutation in the mouse alpha 1 glycine receptor gene (Glra1) results in progressive neurological symptoms and juvenile death. Hum Mol Genet 1994; 3(11):2025-2030.
(98) Saul B, Schmieden V, Kling C, Mulhardt C, Gass P, Kuhse J et al. Point mutation of glycine receptor alpha 1 subunit in the spasmodic mouse affects agonist responses. FEBS Lett 1994; 350(1):71-76.
(99) Ryan SG, Buckwalter MS, Lynch JW, Handford CA, Segura L, Shiang R et al. A missense mutation in the gene encoding the alpha 1 subunit of the inhibitory glycine receptor in the spasmodic mouse. Nat Genet 1994;
7(2):131-135.
(100) Becker L, von Wegerer J, Schenkel J, Zeilhofer HU, Swandulla D, Weiher H.
Disease-specific human glycine receptor alpha1 subunit causes
hyperekplexia phenotype and impaired glycine- and GABA(A)-receptor transmission in transgenic mice. J Neurosci 2002; 22(7):2505-2512.
(101) Ahrens J, Leuwer M, Stachura S, Krampfl K, Belelli D, Lambert JJ et al. A transmembrane residue influences the interaction of propofol with the strychnine-sensitive glycine alpha1 and alpha1beta receptor. Anesth Analg 2008; 107(6):1875-1883.
(102) Yang L, Sonner JM. The anesthetic-like effects of diverse compounds on wild-type and mutant gamma-aminobutyric acid type A and glycine
receptors. Anesth Analg 2008; 106(3):838-45, table.
(103) Mihic SJ, Ye Q, Wick MJ, Koltchine VV, Krasowski MD, Finn SE et al. Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors.
Nature 1997; 389(6649):385-389.
(104) Ye Q, Koltchine VV, Mihic SJ, Mascia MP, Wick MJ, Finn SE et al.
Enhancement of glycine receptor function by ethanol is inversely correlated with molecular volume at position alpha267. J Biol Chem 1998; 273(6):3314-3319.
(105) Wick MJ, Mihic SJ, Ueno S, Mascia MP, Trudell JR, Brozowski SJ et al.
Mutations of gamma-aminobutyric acid and glycine receptors change alcohol cutoff: evidence for an alcohol receptor? Proc Natl Acad Sci U S A 1998;
95(11):6504-6509.
(106) Krasowski MD, Harrison NL. The actions of ether, alcohol and alkane general anaesthetics on GABAA and glycine receptors and the effects of TM2 and TM3 mutations. Br J Pharmacol 2000; 129(4):731-743.
(107) Kay B, Rolly G. I.C.I. 35868, a new intravenous induction agent. Acta Anaesthesiol Belg 1977; 28(4):303-316.
(108) James R, Glen JB. Synthesis, biological evaluation, and preliminary structure-activity considerations of a series of alkylphenols as intravenous anesthetic agents. J Med Chem 1980; 23(12):1350-1357.
(109) Hemmings HC, Jr., Hopkins PM. Foundations of Anesthesia Basic and Clinical Sciences. Book 1999.
(110) Frenkel C, Urban BW. [The molecular action profile of intravenous anesthetics]. Anasthesiol Intensivmed Notfallmed Schmerzther 1992;
27(2):101-108.
(111) Franks NP, Lieb WR. Molecular and cellular mechanisms of general anaesthesia. Nature 1994; 367(6464):607-614.
(112) Wang H, Cork R, Rao A. Development of a new generation of propofol. Curr Opin Anaesthesiol 2007; 20(4):311-315.
(113) Sebel PS, Lowdon JD. Propofol: a new intravenous anesthetic.
Anesthesiology 1989; 71(2):260-277.
(114) Lee TL. Pharmacology of propofol. Ann Acad Med Singapore 1991;
20(1):61-65.
(115) Kanto J, Gepts E. Pharmacokinetic implications for the clinical use of propofol. Clin Pharmacokinet 1989; 17(5):308-326.
(116) Vanlersberghe C, Camu F. Propofol. Handb Exp Pharmacol 2008;(182):227-252.
(117) Dueck MH, Oberthuer A, Wedekind C, Paul M, Boerner U. Propofol impairs the central but not the peripheral part of the motor system. Anesth Analg 2003; 96(2):449-55, table.
(118) Kakinohana M, Fuchigami T, Nakamura S, Kawabata T, Sugahara K.
Propofol reduces spinal motor neuron excitability in humans. Anesth Analg 2002; 94(6):1586-8, table.
(119) Uchida H, Kishikawa K, Collins JG. Effect of propofol on spinal dorsal horn neurons. Comparison with lack of ketamine effects. Anesthesiology 1995;
83(6):1312-1322.
(120) Ewen A, Archer DP, Samanani N, Roth SH. Hyperalgesia during sedation:
effects of barbiturates and propofol in the rat. Can J Anaesth 1995;
42(6):532-540.
(121) Petersen-Felix S, Arendt-Nielsen L, Bak P, Fischer M, Zbinden AM.
Psychophysical and electrophysiological responses to experimental pain may be influenced by sedation: comparison of the effects of a hypnotic (propofol) and an analgesic (alfentanil). Br J Anaesth 1996; 77(2):165-171.
(122) Frolich MA, Price DD, Robinson ME, Shuster JJ, Theriaque DW, Heft MW.
The effect of propofol on thermal pain perception. Anesth Analg 2005;
100(2):481-486.
(123) Anker-Moller E, Spangsberg N, Arendt-Nielsen L, Schultz P, Kristensen MS, Bjerring P. Subhypnotic doses of thiopentone and propofol cause analgesia to experimentally induced acute pain. Br J Anaesth 1991; 66(2):185-188.
(124) Gilron I, Quirion R, Coderre TJ. Pre- versus postinjury effects of intravenous GABAergic anesthetics on formalin-induced Fos immunoreactivity in the rat spinal cord. Anesth Analg 1999; 88(2):414-420.
(125) Urban BW. The site of anesthetic action. Handb Exp Pharmacol 2008;(182):3-29.
(126) Short CE, Bufalari A. Propofol anesthesia. Vet Clin North Am Small Anim Pract 1999; 29(3):747-778.
(127) Servin FS, Raeder JC, Merle JC, Wattwil M, Hanson AL, Lauwers MH et al.
Remifentanil sedation compared with propofol during regional anaesthesia.
Acta Anaesthesiol Scand 2002; 46(3):309-315.
(128) Wilder-Smith OH, Kolletzki M, Wilder-Smith CH. Sedation with intravenous infusions of propofol or thiopentone. Effects on pain perception. Anaesthesia 1995; 50(3):218-222.
(129) Merrill AW, Barter LS, Rudolph U, Eger EI, Antognini JF, Carstens MI et al.
Propofol's effects on nociceptive behavior and spinal c-fos expression after intraplantar formalin injection in mice with a mutation in the
gamma-aminobutyric acid-type(A) receptor beta3 subunit. Anesth Analg 2006;
103(2):478-83, table.
(130) Goto T, Marota JJ, Crosby G. Pentobarbitone, but not propofol, produces pre-emptive analgesia in the rat formalin model. Br J Anaesth 1994;
72(6):662-667.
(131) Kotani Y, Shimazawa M, Yoshimura S, Iwama T, Hara H. The experimental and clinical pharmacology of propofol, an anesthetic agent with
neuroprotective properties. CNS Neurosci Ther 2008; 14(2):95-106.
(132) Trapani G, Altomare C, Liso G, Sanna E, Biggio G. Propofol in anesthesia.
Mechanism of action, structure-activity relationships, and drug delivery. Curr
Mechanism of action, structure-activity relationships, and drug delivery. Curr