Alpha-conotoxins ImI and ImII. Similar alpha 7 nicotinic receptor antagonists act at different sites |
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Authors: | Ellison Michael McIntosh J Michael Olivera Baldomero M |
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Institution: | Department of Biology, University of Utah, Salt Lake City 84112, USA. michael.ellison@m.cc.utah.edu |
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Abstract: | A novel conotoxin, alpha-conotoxin ImII (alpha-CTx ImII), identified from Conus imperialis venom ducts, was chemically synthesized. A previously characterized C. imperialis conotoxin, alpha-conotoxin ImI (alpha-CTx ImI), is closely related; 9 of 12 amino acids are identical. Both alpha-CTx ImII and alpha-CTx ImI functionally inhibit heterologously expressed rat alpha7 nAChRs with similar IC(50) values. Furthermore, the biological activities of intracranially applied alpha-CTx ImI and alpha-CTx ImII are similar over the same dosage range, and are consistent with alpha7 nAChR inhibition. However, unlike alpha-CTx ImI, alpha-CTx ImII was not able to block the binding of alpha-bungarotoxin to alpha7 nAChRs. alpha-Conotoxin ImI and alpha-bungarotoxin-binding sites have been well characterized as overlapping and located at the cleft between adjacent nAChR subunits. Because alpha-CTx ImI and alpha-CTx ImII share extensive sequence homology, the inability of alpha-CTx ImII to compete with alpha-BgTx is surprising. Furthermore, functional studies in oocytes indicate that there is no overlap between functional binding sites of alpha-CTx ImI and alpha-CTx ImII. Like alpha-CTx ImI, the block by alpha-CTx ImII is voltage-independent. Thus, alpha-CTx ImII represents a probe for a novel antagonist binding site, or microsite, on the alpha7 nAChR. |
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