Chemical synthesis and characterization of two α4/7-conotoxins.
α-Conotoxins are small disulfide-constrained peptides that act as potent and selective antagonists on specific subtypes of nicotinic acetylcholine receptors (nAChRs). We previously cloned two α-conotoxins, Mr1.1 from the molluscivorous Conus marmoreus and Lp1.4 from the vermivorous Conus leopardus. Both of them have the typical 4/7-type framework of the subfamily of α-conotoxins that act on neuronal nAChRs. In this work, we chemically synthesized these two toxins and characterized their functional properties. The synthetic Mr1.1 could primarily inhibit acetylcholine (ACh)-evoked currents reversibly in the oocyte-expressed rat α7 nAChR, whereas Lp1.4 was an unexpected specific blocker of the mouse fetal muscle α1β1γδ receptor. Although their inhibition affinities were relatively low, their unique receptor recognition profiles make them valuable tools for toxin-receptor interaction studies. Mr1.1 could also suppress the inflammatory response to pain in vivo, suggesting that it should be further investigated with respect to its molecular role in analgesia and its mechanism or therapeutic target for the treatment of pain.
Peng
Can
C
Institute of Protein Research, Tongji University, Shanghai, China.
Chen
Weihua
W
Sanders
Tanya
T
Chew
Geoffrey
G
Liu
Jing
J
Hawrot
Edward
E
Chi
Chengwu
C
D000109:Acetylcholine / Q000494:pharmacology; D000595:Amino Acid Sequence; D000700:Analgesics / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000494:pharmacology; D002351:Carrageenan; D018679:Cholinergic Agonists / Q000494:pharmacology; D020916:Conotoxins / Q000138:chemical synthesis* / Q000235:genetics / Q000494:pharmacology*; D052078:Conus Snail / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D005260:Female; D006614:Hindlimb / Q000187:drug effects / Q000473:pathology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000517:prevention & control; D008297:Male; D013058:Mass Spectrometry; D008564:Membrane Potentials / Q000187:drug effects; D008969:Molecular Sequence Data; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000235:genetics / Q000502:physiology; D014982:Xenopus laevis
D000700:Analgesics; D002121:Calcium Channel Blockers; D018679:Cholinergic Agonists; D020916:Conotoxins; D011978:Receptors, Nicotinic; D002351:Carrageenan; D000109:Acetylcholine
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