Cloning, Synthesis and Functional Characterization of a Novel ?-Conotoxin Lt1.3.

ABSTRACT: ?-Conotoxins (?-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 ?-CTxs targeting both receptors, the disulfide connectivity arrangement "C¹-C³, C²-C?" is present. In this work, a novel ?4/7-CTx named Lt1.3 (GCCSHPACSGNNPYFC-NH?) 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-C?" and "C¹-C?, C²-C³" were found and functionally characterized. Electrophysiological experiments showed that Lt1.3 containing the common disulfide bridges "C¹-C³, C²-C?" potently and selectively inhibited ?3?2 nAChRs and not GABABR-coupled Cav2.2. Surprisingly, but the isomer with the disulfide bridges "C¹-C?, C²-C³" showed exactly the opposite inhibitory activity, inhibiting only GABABR-coupled Cav2.2 and not ?3?2 nAChRs. These findings expand the knowledge of the targets and selectivity of ?-CTxs and provide a new structural motif to inhibit the GABABR-coupled Cav2.2.

SUBMITTER: Chen J 

PROVIDER: S-EPMC5923399 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature