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Globular and ribbon isomers of Conus geographus α-conotoxins antagonize human nicotinic acetylcholine receptors
- Source :
- Biochemical pharmacology. 190
- Publication Year :
- 2021
-
Abstract
- The short disulfide-rich α-conotoxins derived from the venom of Conus snails comprise a conserved CICII(m)CIII(n)CIV cysteine framework (m and n, number of amino acids) and the majority antagonize nicotinic acetylcholine receptors (nAChRs). Depending on disulfide connectivity, α-conotoxins can exist as either globular (CI-CIII, CII-CIV), ribbon (CI-CIV, CII-CIII) or bead (CI-CII, CIII-CIV) isomers. In the present study, C. geographus α-conotoxins GI, GIB, G1.5 and G1.9 were chemically synthesized as globular and ribbon isomers and their activity investigated at human nAChRs expressed in Xenopus oocytes using the two-electrode voltage clamp recording technique. Both the globular and ribbon isomers of the 3/5 (m/n) α-conotoxins GI and GIB selectively inhibit heterologous human muscle-type α1β1δe nAChRs, whereas G1.5, a 4/7 α-conotoxin, selectively antagonizes neuronal (non-muscle) nAChR subtypes particularly human α3β2, α7 and α9α10 nAChRs. In contrast, globular and ribbon isomers of G1.9, a novel C-terminal elongated 4/8 α-conotoxin exhibited no activity at the human nAChR subtypes studied. This study reinforces earlier observations that 3/5 α-conotoxins selectively target the muscle nAChR subtypes, although interestingly, GIB is also active at α7 and α9 α10 nAChRs. The 4/7 α-conotoxins target human neuronal nAChR subtypes whereas the pharmacology of the 4/8 α-conotoxin remains unknown.
- Subjects :
- 0301 basic medicine
Patch-Clamp Techniques
Xenopus
Nicotinic Antagonists
Receptors, Nicotinic
complex mixtures
Biochemistry
Cone snail
03 medical and health sciences
Xenopus laevis
0302 clinical medicine
Conus
Animals
Humans
Protein Isoforms
Acetylcholine receptor
Pharmacology
chemistry.chemical_classification
biology
Conus geographus
Chemistry
Conus Snail
biology.organism_classification
Amino acid
Nicotinic acetylcholine receptor
Protein Subunits
030104 developmental biology
Nicotinic agonist
nervous system
030220 oncology & carcinogenesis
Biophysics
Oocytes
sense organs
Conotoxins
Subjects
Details
- ISSN :
- 18732968
- Volume :
- 190
- Database :
- OpenAIRE
- Journal :
- Biochemical pharmacology
- Accession number :
- edsair.doi.dedup.....1282f293630faed9882ee4f9422a9c50