Abstract
α-Conotoxins (α-CTxs) are small peptides composed of 11 to 20 amino acid residues with two disulfide bridges. Most of them potently and selectively target nicotinic acetylcholine receptor (nAChR) subtypes, and a few were found to inhibit the GABAB receptor (GABABR)-coupled N-type calcium channels (Cav2.2). However, in all of α-CTxs targeting both receptors, the disulfide connectivity arrangement “C1-C3, C2-C4” is present. In this work, a novel α4/7-CTx named Lt1.3 (GCCSHPACSGNNPYFC-NH2) was cloned from the venom ducts of Conus litteratus (C. litteratus) in the South China Sea. Lt1.3 was then chemically synthesized and two isomers with disulfide bridges “C1-C3, C2-C4” and “C1-C4, C2-C3” were found and functionally characterized. Electrophysiological experiments showed that Lt1.3 containing the common disulfide bridges “C1-C3, C2-C4” potently and selectively inhibited α3β2 nAChRs and not GABABR-coupled Cav2.2. Surprisingly, but the isomer with the disulfide bridges “C1-C4, C2-C3” showed exactly the opposite inhibitory activity, inhibiting only GABABR-coupled Cav2.2 and not α3β2 nAChRs. These findings expand the knowledge of the targets and selectivity of α-CTxs and provide a new structural motif to inhibit the GABABR-coupled Cav2.2.
Highlights
Conotoxins (CTx) are small, disulfide-rich peptides secreted by venom salivary glands of marine cone snails, whose precursors are encoded by various gene superfamilies [1,2]
The results showed that Lt1.3-II (C1 -C3, C2 -C4 ) potently and selectively inhibited α3β2 nicotinic acetylcholine receptor (nAChR), but the isomer Lt1.3-I (C1 -C4, C2 -C3 ) did not
A novel α-CTx precursor was isolated from the genomic DNA of C. litteratus (Figure 1)
Summary
Conotoxins (CTx) are small, disulfide-rich peptides secreted by venom salivary glands of marine cone snails, whose precursors are encoded by various gene superfamilies [1,2]. Based on the consensus signal sequences of precursors, the number of cysteine residues and the arrangement of the disulfide bonds, CTx are categorized into various super-families (A, B, C, D, E, I, M, O, P, S, T, etc.) [1,2]. Some conotoxins potently and selectively target a wide variety of ion channels, including sodium (Na+ )-, potassium (K+ )-, and calcium (Ca2+ )-channels [3,4,5]. A receptor (GABAA R) [10]. They are highly valuable for neuropharmacological probes and drug development leads [11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
