Segmental exchanges define 4-aminopyridine binding and the inner mouth of K + pores
4-Aminopyridine (4AP) blocks the intracellular mouth of voltage-gated K + channels. We identified critical regions for 4AP binding with chimeric channels in which segments of a low affinity clone (Kv2.1, IC 50 = 18 mM) were replaced with those of a high affinity clone (Kv3.1, IC 50 = 0.1 mM) 4AP sen...
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| Veröffentlicht in: | Neuron (Cambridge, Mass.) Mass.), 1993-09, Vol.11 (3), p.503-512 |
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| container_title | Neuron (Cambridge, Mass.) |
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| creator | Kirsch, G.E. Shieh, C.-C. Drewe, J.A. Vener, D.F. Brownt, A.M. |
| description | 4-Aminopyridine (4AP) blocks the intracellular mouth of voltage-gated K
+ channels. We identified critical regions for 4AP binding with chimeric channels in which segments of a low affinity clone (Kv2.1, IC
50 = 18 mM) were replaced with those of a high affinity clone (Kv3.1, IC
50 = 0.1 mM) 4AP sensitivity was not tranferred with the S5–S6 linker (pore or P region) Instead, a chimera of the cytoplasmic half of S6 increased block 20-fold, without affecting gating.A double chimera of the cytoplasmic halves of S5 and S6 fully transferred 4AP sensitivity. Because 4AP block was inhibited by tetrapentylammonium, we conclude that determinants of 4AP binding lie in the S6 segment that forms the cytoplasmic vestibule of the pore and that this site may overlap a quaternary ammonium site. |
| doi_str_mv | 10.1016/0896-6273(93)90154-J |
| format | Article |
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50 = 18 mM) were replaced with those of a high affinity clone (Kv3.1, IC
50 = 0.1 mM) 4AP sensitivity was not tranferred with the S5–S6 linker (pore or P region) Instead, a chimera of the cytoplasmic half of S6 increased block 20-fold, without affecting gating.A double chimera of the cytoplasmic halves of S5 and S6 fully transferred 4AP sensitivity. Because 4AP block was inhibited by tetrapentylammonium, we conclude that determinants of 4AP binding lie in the S6 segment that forms the cytoplasmic vestibule of the pore and that this site may overlap a quaternary ammonium site.</description><identifier>ISSN: 0896-6273</identifier><identifier>EISSN: 1097-4199</identifier><identifier>DOI: 10.1016/0896-6273(93)90154-J</identifier><identifier>PMID: 8398143</identifier><identifier>CODEN: NERNET</identifier><language>eng</language><publisher>Cambridge, MA: Elsevier Inc</publisher><subject>4-Aminopyridine - metabolism ; 4-Aminopyridine - pharmacology ; Amino Acid Sequence ; Binding, Competitive ; Biological and medical sciences ; Cell physiology ; Chimera ; Fundamental and applied biological sciences. Psychology ; Intracellular Membranes - metabolism ; Ion Channel Gating ; Membrane and intracellular transports ; Molecular and cellular biology ; Molecular Sequence Data ; Mutation ; Potassium Channels - drug effects ; Potassium Channels - genetics ; Potassium Channels - metabolism ; Quaternary Ammonium Compounds - metabolism</subject><ispartof>Neuron (Cambridge, Mass.), 1993-09, Vol.11 (3), p.503-512</ispartof><rights>1993</rights><rights>1994 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c386t-984077c70b75b2e775eb233c6018cf26338c5763f41a5b6de49e0e7923ea1bc83</citedby><cites>FETCH-LOGICAL-c386t-984077c70b75b2e775eb233c6018cf26338c5763f41a5b6de49e0e7923ea1bc83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/089662739390154J$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,65309</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=3768904$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8398143$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kirsch, G.E.</creatorcontrib><creatorcontrib>Shieh, C.-C.</creatorcontrib><creatorcontrib>Drewe, J.A.</creatorcontrib><creatorcontrib>Vener, D.F.</creatorcontrib><creatorcontrib>Brownt, A.M.</creatorcontrib><title>Segmental exchanges define 4-aminopyridine binding and the inner mouth of K + pores</title><title>Neuron (Cambridge, Mass.)</title><addtitle>Neuron</addtitle><description>4-Aminopyridine (4AP) blocks the intracellular mouth of voltage-gated K
+ channels. We identified critical regions for 4AP binding with chimeric channels in which segments of a low affinity clone (Kv2.1, IC
50 = 18 mM) were replaced with those of a high affinity clone (Kv3.1, IC
50 = 0.1 mM) 4AP sensitivity was not tranferred with the S5–S6 linker (pore or P region) Instead, a chimera of the cytoplasmic half of S6 increased block 20-fold, without affecting gating.A double chimera of the cytoplasmic halves of S5 and S6 fully transferred 4AP sensitivity. Because 4AP block was inhibited by tetrapentylammonium, we conclude that determinants of 4AP binding lie in the S6 segment that forms the cytoplasmic vestibule of the pore and that this site may overlap a quaternary ammonium site.</description><subject>4-Aminopyridine - metabolism</subject><subject>4-Aminopyridine - pharmacology</subject><subject>Amino Acid Sequence</subject><subject>Binding, Competitive</subject><subject>Biological and medical sciences</subject><subject>Cell physiology</subject><subject>Chimera</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Intracellular Membranes - metabolism</subject><subject>Ion Channel Gating</subject><subject>Membrane and intracellular transports</subject><subject>Molecular and cellular biology</subject><subject>Molecular Sequence Data</subject><subject>Mutation</subject><subject>Potassium Channels - drug effects</subject><subject>Potassium Channels - genetics</subject><subject>Potassium Channels - metabolism</subject><subject>Quaternary Ammonium Compounds - metabolism</subject><issn>0896-6273</issn><issn>1097-4199</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1993</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kNtKxDAQhoMouh7eQCEXIopUkybN4UYQ8Sx4oV6HNJ3uRtp0Tbqib2_LLnspDAzD_80wfAgdUnJBCRWXRGmRiVyyU83ONKEFz5420IQSLTNOtd5EkzWyg3ZT-iSE8kLTbbStmFaUswl6e4NpC6G3DYYfN7NhCglXUPsAmGe29aGb_0ZfjXPpw9Cn2IYK9zPAPgSIuO0W_Qx3NX7G53jeRUj7aKu2TYKDVd9DH3e37zcP2cvr_ePN9UvmmBJ9phUnUjpJSlmUOUhZQJkz5gShytW5YEy5QgpWc2qLUlTANRCQOmdgaekU20Mny7vz2H0tIPWm9clB09gA3SIZWWhJWa4HkC9BF7uUItRmHn1r46-hxIwuzSjKjKKMHmp0aZ6GtaPV_UXZQrVeWskb8uNVbpOzTR1tcD6tMSaF0oQP2NUSg8HFt4dokvMQHFQ-gutN1fn___gDxnyO1A</recordid><startdate>19930901</startdate><enddate>19930901</enddate><creator>Kirsch, G.E.</creator><creator>Shieh, C.-C.</creator><creator>Drewe, J.A.</creator><creator>Vener, D.F.</creator><creator>Brownt, A.M.</creator><general>Elsevier Inc</general><general>Cell Press</general><scope>IQODW</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>7X8</scope></search><sort><creationdate>19930901</creationdate><title>Segmental exchanges define 4-aminopyridine binding and the inner mouth of K + pores</title><author>Kirsch, G.E. ; Shieh, C.-C. ; Drewe, J.A. ; Vener, D.F. ; Brownt, A.M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c386t-984077c70b75b2e775eb233c6018cf26338c5763f41a5b6de49e0e7923ea1bc83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1993</creationdate><topic>4-Aminopyridine - metabolism</topic><topic>4-Aminopyridine - pharmacology</topic><topic>Amino Acid Sequence</topic><topic>Binding, Competitive</topic><topic>Biological and medical sciences</topic><topic>Cell physiology</topic><topic>Chimera</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Intracellular Membranes - metabolism</topic><topic>Ion Channel Gating</topic><topic>Membrane and intracellular transports</topic><topic>Molecular and cellular biology</topic><topic>Molecular Sequence Data</topic><topic>Mutation</topic><topic>Potassium Channels - drug effects</topic><topic>Potassium Channels - genetics</topic><topic>Potassium Channels - metabolism</topic><topic>Quaternary Ammonium Compounds - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kirsch, G.E.</creatorcontrib><creatorcontrib>Shieh, C.-C.</creatorcontrib><creatorcontrib>Drewe, J.A.</creatorcontrib><creatorcontrib>Vener, D.F.</creatorcontrib><creatorcontrib>Brownt, A.M.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Neuron (Cambridge, Mass.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kirsch, G.E.</au><au>Shieh, C.-C.</au><au>Drewe, J.A.</au><au>Vener, D.F.</au><au>Brownt, A.M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Segmental exchanges define 4-aminopyridine binding and the inner mouth of K + pores</atitle><jtitle>Neuron (Cambridge, Mass.)</jtitle><addtitle>Neuron</addtitle><date>1993-09-01</date><risdate>1993</risdate><volume>11</volume><issue>3</issue><spage>503</spage><epage>512</epage><pages>503-512</pages><issn>0896-6273</issn><eissn>1097-4199</eissn><coden>NERNET</coden><abstract>4-Aminopyridine (4AP) blocks the intracellular mouth of voltage-gated K
+ channels. We identified critical regions for 4AP binding with chimeric channels in which segments of a low affinity clone (Kv2.1, IC
50 = 18 mM) were replaced with those of a high affinity clone (Kv3.1, IC
50 = 0.1 mM) 4AP sensitivity was not tranferred with the S5–S6 linker (pore or P region) Instead, a chimera of the cytoplasmic half of S6 increased block 20-fold, without affecting gating.A double chimera of the cytoplasmic halves of S5 and S6 fully transferred 4AP sensitivity. Because 4AP block was inhibited by tetrapentylammonium, we conclude that determinants of 4AP binding lie in the S6 segment that forms the cytoplasmic vestibule of the pore and that this site may overlap a quaternary ammonium site.</abstract><cop>Cambridge, MA</cop><pub>Elsevier Inc</pub><pmid>8398143</pmid><doi>10.1016/0896-6273(93)90154-J</doi><tpages>10</tpages></addata></record> |
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| subjects | 4-Aminopyridine - metabolism 4-Aminopyridine - pharmacology Amino Acid Sequence Binding, Competitive Biological and medical sciences Cell physiology Chimera Fundamental and applied biological sciences. Psychology Intracellular Membranes - metabolism Ion Channel Gating Membrane and intracellular transports Molecular and cellular biology Molecular Sequence Data Mutation Potassium Channels - drug effects Potassium Channels - genetics Potassium Channels - metabolism Quaternary Ammonium Compounds - metabolism |
| title | Segmental exchanges define 4-aminopyridine binding and the inner mouth of K + pores |
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