Alpha-conotoxins ImI and ImII. Similar alpha 7 nicotinic receptor antagonists act at different sites.
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.
Ellison
Michael
M
Department of Biology, University of Utah, Salt Lake City 84112, USA. michael.ellison@m.cc.utah.edu
McIntosh
J Michael
JM
Olivera
Baldomero M
BM
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001667:Binding, Competitive; D002038:Bungarotoxins / Q000378:metabolism; D020916:Conotoxins / Q000737:chemistry / Q000494:pharmacology*; D008969:Molecular Sequence Data; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3
D002038:Bungarotoxins; D020916:Conotoxins; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; C471178:alpha-conotoxin ImII, Conus imperialis; C087686:alpha-conotoxin ImI