Molecular Dynamics Simulation Links Conformation of a Pore-Flanking Region to Hyperekplexia-Related Dysfunction of the Inhibitory Glycine Receptor
Inhibitory glycine receptors mediate rapid synaptic inhibition in mammalian spinal cord and brainstem. The previously identified hyperekplexia mutation GLRA1(P250T), located within the intracellular TM1-2 loop of the GlyR α1 subunit, results in altered receptor activation and desensitization. Here,...
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| Veröffentlicht in: | Chemistry & biology 2004-10, Vol.11 (10), p.1339-1350 |
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| creator | Breitinger, Hans-Georg Lanig, Harald Vohwinkel, Christine Grewer, Christof Breitinger, Ulrike Clark, Tim Becker, Cord-Michael |
| description | Inhibitory glycine receptors mediate rapid synaptic inhibition in mammalian spinal cord and brainstem. The previously identified hyperekplexia mutation
GLRA1(P250T), located within the intracellular TM1-2 loop of the GlyR α1 subunit, results in altered receptor activation and desensitization. Here, elementary steps of ion channel function of α1(250) mutants were resolved and shown to correlate with hydropathy and molar volume of residue α1(250). Single-channel recordings and rapid activation kinetic studies using laser pulse photolysis showed reduced conductance but similar open probability of α1(P250T) mutant channels. Molecular dynamics simulation of a helix-turn-helix motif representing the intracellular TM1-2 domain revealed alterations in backbone conformation, indicating an increased flexibility in these mutants that paralleled changes in elementary steps of channel function. Thus, the architecture of the TM1-2 loop is a critical determinant of ion channel conductance and receptor desensitization. |
| doi_str_mv | 10.1016/j.chembiol.2004.07.008 |
| format | Article |
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GLRA1(P250T), located within the intracellular TM1-2 loop of the GlyR α1 subunit, results in altered receptor activation and desensitization. Here, elementary steps of ion channel function of α1(250) mutants were resolved and shown to correlate with hydropathy and molar volume of residue α1(250). Single-channel recordings and rapid activation kinetic studies using laser pulse photolysis showed reduced conductance but similar open probability of α1(P250T) mutant channels. Molecular dynamics simulation of a helix-turn-helix motif representing the intracellular TM1-2 domain revealed alterations in backbone conformation, indicating an increased flexibility in these mutants that paralleled changes in elementary steps of channel function. Thus, the architecture of the TM1-2 loop is a critical determinant of ion channel conductance and receptor desensitization.</description><subject>Cell Line</subject><subject>Computer Simulation</subject><subject>Dose-Response Relationship, Drug</subject><subject>Glycine - metabolism</subject><subject>Glycine - pharmacology</subject><subject>Helix-Turn-Helix Motifs - genetics</subject><subject>Humans</subject><subject>Ion Channels - antagonists & inhibitors</subject><subject>Ion Channels - genetics</subject><subject>Models, Molecular</subject><subject>Mutagenesis, Site-Directed</subject><subject>Myoclonus - genetics</subject><subject>Myoclonus - physiopathology</subject><subject>Neural Inhibition - genetics</subject><subject>Patch-Clamp Techniques</subject><subject>Protein Conformation</subject><subject>Protein Subunits - chemistry</subject><subject>Protein Subunits - genetics</subject><subject>Protein Subunits - physiology</subject><subject>Receptors, Glycine - chemistry</subject><subject>Receptors, Glycine - genetics</subject><subject>Receptors, Glycine - physiology</subject><subject>Reflex, Startle - genetics</subject><subject>Stiff-Person Syndrome - genetics</subject><subject>Stiff-Person Syndrome - physiopathology</subject><subject>Thermodynamics</subject><issn>1074-5521</issn><issn>1879-1301</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUU1v1DAQtRAVLYW_UPnELcHe2E5yAy30Q1pEVeBsOZNJ17uJHewENX-DX1yvdiuOnGb05r03mnmEXHGWc8bVx10OWxwa6_t8xZjIWZkzVr0iF7wq64wXjL9OPStFJuWKn5O3Me4YY7yq1RtyzqWoaq74Bfn7zfcIc28C_bI4M1iI9IcdEjBZ7-jGun2ka-86H4Yj5Dtq6L0PmF33xu2te6QP-HiYTJ7eLiMG3I89PlmTPWCywTY5x2528CKftkjv3NY2dvJhoTf9AtZhcgEcE_KOnHWmj_j-VC_Jr-uvP9e32eb7zd368yYDIYopKwojpGkBS1M1ssKVqTkY1pjaCACleNfwlTSAdSkKkAqBCSVVhW1ZiLqUxSX5cPQdg_89Y5z0YCNgn65CP0fNS6EqKepEVEciBB9jwE6PwQ4mLJozfUhD7_RLGvqQhmalTmkk4dVpw9wM2P6Tnd6fCJ-OBEx3_rEYdASLDrC1AWHSrbf_2_EMzCeiTw</recordid><startdate>20041001</startdate><enddate>20041001</enddate><creator>Breitinger, Hans-Georg</creator><creator>Lanig, Harald</creator><creator>Vohwinkel, Christine</creator><creator>Grewer, Christof</creator><creator>Breitinger, Ulrike</creator><creator>Clark, Tim</creator><creator>Becker, Cord-Michael</creator><general>Elsevier Ltd</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope></search><sort><creationdate>20041001</creationdate><title>Molecular Dynamics Simulation Links Conformation of a Pore-Flanking Region to Hyperekplexia-Related Dysfunction of the Inhibitory Glycine Receptor</title><author>Breitinger, Hans-Georg ; 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The previously identified hyperekplexia mutation
GLRA1(P250T), located within the intracellular TM1-2 loop of the GlyR α1 subunit, results in altered receptor activation and desensitization. Here, elementary steps of ion channel function of α1(250) mutants were resolved and shown to correlate with hydropathy and molar volume of residue α1(250). Single-channel recordings and rapid activation kinetic studies using laser pulse photolysis showed reduced conductance but similar open probability of α1(P250T) mutant channels. Molecular dynamics simulation of a helix-turn-helix motif representing the intracellular TM1-2 domain revealed alterations in backbone conformation, indicating an increased flexibility in these mutants that paralleled changes in elementary steps of channel function. Thus, the architecture of the TM1-2 loop is a critical determinant of ion channel conductance and receptor desensitization.</abstract><cop>United States</cop><pub>Elsevier Ltd</pub><pmid>15489161</pmid><doi>10.1016/j.chembiol.2004.07.008</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Cell Line Computer Simulation Dose-Response Relationship, Drug Glycine - metabolism Glycine - pharmacology Helix-Turn-Helix Motifs - genetics Humans Ion Channels - antagonists & inhibitors Ion Channels - genetics Models, Molecular Mutagenesis, Site-Directed Myoclonus - genetics Myoclonus - physiopathology Neural Inhibition - genetics Patch-Clamp Techniques Protein Conformation Protein Subunits - chemistry Protein Subunits - genetics Protein Subunits - physiology Receptors, Glycine - chemistry Receptors, Glycine - genetics Receptors, Glycine - physiology Reflex, Startle - genetics Stiff-Person Syndrome - genetics Stiff-Person Syndrome - physiopathology Thermodynamics |
| title | Molecular Dynamics Simulation Links Conformation of a Pore-Flanking Region to Hyperekplexia-Related Dysfunction of the Inhibitory Glycine Receptor |
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