Novel conotoxins from Conus striatus and Conus kinoshitai selectively block TTX-resistant sodium channels.
The peptides isolated from venoms of predatory marine Conus snails ("conotoxins") are well-known to be highly potent and selective pharmacological agents for voltage-gated ion channels and receptors. We report the discovery of two novel TTX-resistant sodium channel blockers, mu-conotoxins SIIIA and KIIIA, from two species of cone snails. The two toxins were identified and characterized by combining molecular techniques and chemical synthesis. Both peptides inhibit TTX-resistant sodium currents in neurons of frog sympathetic and dorsal root ganglia but poorly block action potentials in frog skeletal muscle, which are mediated by TTX-sensitive sodium channels. The amino acid sequences in the C-terminal region of the two peptides and of the previously characterized mu-conotoxin SmIIIA (which also blocks TTX-resistant channels) are similar, but the three peptides differ in the length of their first N-terminal loop. We used molecular dynamics simulations to analyze how altering the number of residues in the first loop affects the overall structure of mu-conotoxins. Our results suggest that the naturally occurring truncations do not affect the conformation of the C-terminal loops. Taken together, structural and functional differences among mu-conotoxins SmIIIA, SIIIA, and KIIIA offer a unique insight into the "evolutionary engineering" of conotoxin activity.
Bulaj
Grzegorz
G
Department of Biology, University of Utah, Salt Lake City, Utah 84112, USA. bulaj@biology.utah.edu
West
Peter J
PJ
Garrett
James E
JE
Watkins
Maren
M
Marsh
Maren
M
Zhang
Min-Min
MM
Norton
Raymond S
RS
Smith
Brian J
BJ
Yoshikami
Doju
D
Olivera
Baldomero M
BM
D000200:Action Potentials / Q000187:drug effects; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D020916:Conotoxins / Q000737:chemistry* / Q000302:isolation & purification* / Q000494:pharmacology; D005260:Female; D005727:Ganglia, Spinal / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D005728:Ganglia, Sympathetic / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D008978:Mollusk Venoms / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology; D009479:Neuropeptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D011894:Rana pipiens; D026941:Sodium Channel Blockers / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism; D013779:Tetrodotoxin / Q000737:chemistry / Q000494:pharmacology*
D020916:Conotoxins; D008978:Mollusk Venoms; D009479:Neuropeptides; D010446:Peptide Fragments; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C502265:mu-conotoxin KIIIA, Conus kinoshitai; C470785:mu-conotoxin SmIIIA; D013779:Tetrodotoxin