A novel alpha-conotoxin identified by gene sequencing is active in suppressing the vascular response to selective stimulation of sensory nerves in vivo.
We describe the identification of a conopeptide sequence in venom duct mRNA from Conus victoriae that suppresses a vascular response to pain in the rat. PCR-RACE was used to screen venom duct cDNAs for those transcripts that encode specific antagonists of vertebrate neuronal nicotinic acetylcholine receptors (nAChRs). One of these peptides, Vc1.1, was active as an antagonist of neuronal nAChRs in receptor binding and functional studies in bovine chromaffin cells. It also suppressed the vascular responses to unmyelinated sensory nerve C-fiber activation in rats. Such vascular responses are involved in pain transmission. Furthermore, its ability to suppress C-fiber function was greater than that of MVIIA, an omega-conotoxin with known analgesic activity in rats and humans. Vc1.1 has a high degree of sequence similarity to the alpha-conotoxin family of peptides and has the 4,7 loop structure characteristic of the subfamily of peptides that act on neuronal-type nAChRs. The results suggest that neuronal alpha-conotoxins should be further investigated with respect to their potential to suppress pain.
Sandall
D W
DW
Department of Biochemistry and Molecular Biology and National Ageing Research Institute, The University of Melbourne, Victoria 3010, Australia.
Satkunanathan
N
N
Keays
D A
DA
Polidano
M A
MA
Liping
X
X
Pham
V
V
Down
J G
JG
Khalil
Z
Z
Livett
B G
BG
Gayler
K R
KR
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002417:Cattle; D019439:Chromaffin Cells / Q000187:drug effects / Q000378:metabolism; D020916:Conotoxins / Q000235:genetics* / Q000494:pharmacology*; D018076:DNA, Complementary / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D008297:Male; D008969:Molecular Sequence Data; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects* / Q000502:physiology; D009469:Neuromuscular Junction / Q000187:drug effects / Q000502:physiology; D009475:Neurons, Afferent / Q000187:drug effects* / Q000502:physiology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D016133:Polymerase Chain Reaction / Q000379:methods; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000502:physiology; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D020960:omega-Conotoxins / Q000494:pharmacology
D020916:Conotoxins; D018076:DNA, Complementary; D018733:Nicotinic Antagonists; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D020960:omega-Conotoxins; C078452:ziconotide