dc.contributor.author | Lewis, Richard J | |
dc.contributor.author | Schroeder, Christina I | |
dc.contributor.author | Ekberg, Jenny | |
dc.contributor.author | Nielsen, Katherine J | |
dc.contributor.author | Loughnan, Marion | |
dc.contributor.author | Thomas, Linda | |
dc.contributor.author | Adams, Denise A | |
dc.contributor.author | Drinkwater, Roger | |
dc.contributor.author | Adams, David J | |
dc.contributor.author | Alewood, Paul F | |
dc.date.accessioned | 2017-05-03T16:58:36Z | |
dc.date.available | 2017-05-03T16:58:36Z | |
dc.date.issued | 2007 | |
dc.identifier.issn | 0026-895X | |
dc.identifier.doi | 10.1124/mol.106.028225 | |
dc.identifier.uri | http://hdl.handle.net/10072/28093 | |
dc.description.abstract | μ-Conotoxins are three-loop peptides produced by cone snails to inhibit voltage-gated sodium channels during prey capture. Using polymerase chain reaction techniques, we identified a gene sequence from the venom duct of Conus tulipa encoding a new μ-conotoxin-TIIIA (TIIIA). A 125I-TIIIA binding assay was established to isolate native TIIIA from the crude venom of Conus striatus. The isolated peptide had three post-translational modifications, including two hydroxyproline residues and C-terminal amidation, and <35% homology to other μ-conotoxins. TIIIA potently displaced [3H]saxitoxin and 125I-TIIIA from rat brain (Nav1.2) and skeletal muscle (Nav1.4) membranes. Alanine and glutamine scans of TIIIA revealed several residues, including Arg14, that were critical for high-affinity binding to tetrodotoxin (TTX)-sensitive Na+ channels. We were surprised to find that [E15A]TIIIA had a 10-fold higher affinity than TIIIA for TTX-sensitive sodium channels (IC50, 15 vs. 148 pM at rat brain membrane). TIIIA was selective for Nav1.2 and -1.4 over Nav1.3, -1.5, -1.7, and -1.8 expressed in Xenopus laevis oocytes and had no effect on rat dorsal root ganglion neuron Na+ current. 1H NMR studies revealed that TIIIA adopted a single conformation in solution that was similar to the major conformation described previously for μ-conotoxin PIIIA. TIIIA and analogs provide new biochemical probes as well as insights into the structure-activity of μ-conotoxins. | |
dc.description.peerreviewed | Yes | |
dc.description.publicationstatus | Yes | |
dc.language | English | |
dc.language.iso | eng | |
dc.publisher | The American Society for Pharmacology and Experimental Therapeutics | |
dc.publisher.place | The United States of America | |
dc.relation.ispartofstudentpublication | N | |
dc.relation.ispartofpagefrom | 676 | |
dc.relation.ispartofpageto | 685 | |
dc.relation.ispartofissue | 3 | |
dc.relation.ispartofjournal | Molecular Pharmacology | |
dc.relation.ispartofvolume | 71 | |
dc.rights.retention | Y | |
dc.subject.fieldofresearch | Biochemistry and cell biology | |
dc.subject.fieldofresearch | Neurosciences | |
dc.subject.fieldofresearch | Pharmacology and pharmaceutical sciences | |
dc.subject.fieldofresearchcode | 3101 | |
dc.subject.fieldofresearchcode | 3209 | |
dc.subject.fieldofresearchcode | 3214 | |
dc.title | Isolation and Structure-Activity of μ-Conotoxin TIIIA, A Potent Inhibitor of Tetrodotoxin-Sensitive Voltage-Gated Sodium Channels | |
dc.type | Journal article | |
dc.type.description | C1 - Articles | |
dc.type.code | C - Journal Articles | |
gro.rights.copyright | Self-archiving of the author-manuscript version is not yet supported by this journal. Please refer to the journal link for access to the definitive, published version or contact the author[s] for more information. | |
gro.date.issued | 2015-05-13T03:18:30Z | |
gro.hasfulltext | No Full Text | |
gro.griffith.author | Ekberg, Jenny A. | |