Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 278, Issue 2, Pages 757-764Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M204565200
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Funding
- NIGMS NIH HHS [GM08537, GM48677] Funding Source: Medline
- NIMH NIH HHS [MH53631] Funding Source: Medline
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A novel conotoxin, alpha-conotoxin Imll (alpha-CTx Imll), 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 ImH and alpha-CTx ImI functionally inhibit heterologously expressed rat alpha7 nAChRs with similar IC50 values. Furthermore, the biological activities of intracranially applied alpha-CTx Iml and alpha-CTx ImH are similar over the same dosage range, and are consistent with a7 nAChR inhibition. However, unlike a-CTx ImI, a-CTx Imll was not able to block the binding of a-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 Iml and alpha-CTx ImH share extensive sequence homology, the inability of alpha-CTx ImH 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 Iml and alpha-CTx Imll. Like alpha-CTx Iml, the block by alpha-CTx Imll 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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