Structural and functional diversities among mu-conotoxins targeting TTX-resistant sodium channels

Zhang, MM; Fiedler, B; Green, BR; Catlin, P; Watkins, M; Garrett, JE; Smith, BJ; Yoshikami, D; Olivera, BM; Bulaj, G

Author(s): Zhang, MM; Fiedler, B; Green, BR; Catlin, P; Watkins, M; Garrett, JE; Smith, BJ; Yoshikami, D; Olivera, BM; Bulaj, G;
Details: Publication Year 2006-03-21,Volume 45,Issue #11,Page 3723-3732
Journal Title: BIOCHEMISTRY
Publication Type: Journal Article
Abstract: mu-Conotoxins are peptides that block sodium channels. Molecular cloning was used to identify four novel mu-conotoxins: CnIIIA, CnIIIB, CIIIA, and MIIIA from Conus consors, C. catus and C. magus. A comparison of their sequences with those of previously characterized mu-conotoxins suggested that the new mu-conotoxins were likely to target tetrodotoxin-resistant (TTX-r) sodium channels. The four peptides were chemically synthesized, and their biological activities were characterized. The new conotoxins all blocked, albeit with varying potencies, TTX-r sodium currents in frog dorsal-root-ganglion (DRG) neurons. The more potent of the four new mu-conotoxins, CnIIIA and CIIIA, exhibited a strikingly different selectivity profile in blocking TTX-r versus TTX-sensitive channels, as determined by their ability to block extracellularly recorded action potentials in three preparations from frog: skeletal muscle. cardiac muscle and TTX-treated C-fibers. CnIIIA was highly specific for TTX-r sodium channels. whereas CIIIA was nonselective. Both peptides appeared significantly less potent in blocking TTX-r sodium currents in rat and mouse DRG neurons. When CnIIIA and CIIIA were injected intracranially into mice, both induced seizures, but only CIIIA caused paralysis. This is the most comprehensive characterization to date of the structural and functional diversities of an emerging group of mu-conotoxins targeting TTX-r sodium channels.
Publisher: AMER CHEMICAL SOC
Keywords: CONUS-GEOGRAPHUS; SENSORY NEURONS; NERVOUS-SYSTEM; GIIIA; PIIIA; PAIN; DISCRIMINATE; ARRANGEMENT; INHIBITOR; PEPTIDES
Publisher's Version: https://doi.org/10.1021/bi052162j
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2006-03-21 12:00:00