A novel conotoxin from Conus striatus, mu-SIIIA, selectively blocking rat tetrodotoxin-resistant sodium channels.
Mu-conotoxin SIIIA, a novel blocker of tetrodotoxin-resistant (TTX-R) voltage-gated sodium channels (VGSCs) has been identified from the fish-hunting cone snail, Conus striatus. The deduced sequence consists of a 20-residue signal peptide, a 31-residue pro-peptide, and a 20-residue mature toxin with its N-terminal Gln cyclized and C-terminus amidated. Mu-SIIIA shares the common cysteine arrangement with other mu-conotoxins. Besides, it exhibits high sequence homology with mu-SmIIIA, a toxin recently characterized from C. stercusmuscarum which potently blocks the TTX-R VGSCs in frog neurons. With whole-cell recording, mu-SIIIA potently and selectively inhibits the TTX-R VGSCs of dissociated adult rat small-diameter dorsal root ganglia (DRG) neurons with a dose- and time-dependent property and irreversibly. Homology-based modeling of mu-PIIIA, SIIIA and SmIIIA implies that they share a common backbone conformation except at the N termini. The hydroxyl-proline residue only present in mu-PIIIA is absent and substituted by an Asp residue in mu-SIIIA and SmIIIA. Similarly, one crucial basic residue (Arg12 in mu-PIIIA) is replaced by serine in the latter two toxins. Such differences might endow them with the capacity to selectively inhibit TTX-S or TTX-R VGSCs. Considering that TTX-R VGSCs predominantly expressed in DRG neurons play pivotal roles in the nociceptive information transmission and that their specific antagonists are still lacking, mu-SIIIA might provide a useful tool for functional studies of these channels, and potentially be developed as an efficient pain killer.
Wang
Cheng-Zhong
CZ
Key Laboratory of Proteomics, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Zhang
Hua
H
Jiang
Hui
H
Lu
Wuyuan
W
Zhao
Zhi-Qi
ZQ
Chi
Cheng-Wu
CW
D000595:Amino Acid Sequence; D000818:Animals; D001224:Aspartic Acid / Q000737:chemistry; D001483:Base Sequence; D020916:Conotoxins / Q000494:pharmacology*; D052078:Conus Snail / Q000737:chemistry*; D003545:Cysteine / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005973:Glutamine / Q000737:chemistry; D006909:Hydroxyproline / Q000737:chemistry; D008969:Molecular Sequence Data; D009420:Nervous System / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D012694:Serine / Q000737:chemistry; D026941:Sodium Channel Blockers / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D015222:Sodium Channels / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013779:Tetrodotoxin / Q000494:pharmacology
D020916:Conotoxins; D010446:Peptide Fragments; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C470785:mu-conotoxin SmIIIA; D005973:Glutamine; D001224:Aspartic Acid; D013779:Tetrodotoxin; D012694:Serine; D003545:Cysteine; D006909:Hydroxyproline