Variable peptide processing of a Conus (Asprella) neocostatus α-conotoxin generates bioactive toxiforms that are potent against distinct nicotinic acetylcholine receptor subtypes.
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| Format: | Artículo científico |
| Langue: | en |
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Biochemical pharmacology
2025
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| author | Ramones, Cydee Marie V Taguchi, Ryoichi S Gamba, Ella Mae E Johann E Isagan, Abe Ernest Watkins, Maren Chicote, Meljune O Velarde, Michael C Villaraza, Aaron Joseph L Yu, Eizadora T Olivera, Baldomero M Concepcion, Gisela P Lluisma, Arturo O |
| author_facet | Ramones, Cydee Marie V Taguchi, Ryoichi S Gamba, Ella Mae E Johann E Isagan, Abe Ernest Watkins, Maren Chicote, Meljune O Velarde, Michael C Villaraza, Aaron Joseph L Yu, Eizadora T Olivera, Baldomero M Concepcion, Gisela P Lluisma, Arturo O Ramones, Cydee Marie V Taguchi, Ryoichi S Gamba, Ella Mae E Johann E Isagan, Abe Ernest Watkins, Maren Chicote, Meljune O Velarde, Michael C Villaraza, Aaron Joseph L Yu, Eizadora T Olivera, Baldomero M Concepcion, Gisela P Lluisma, Arturo O |
| collection | PubMed - marine biology |
| contents | Variable peptide processing of a Conus (Asprella) neocostatus α-conotoxin generates bioactive toxiforms that are potent against distinct nicotinic acetylcholine receptor subtypes. Ramones, Cydee Marie V Taguchi, Ryoichi S Gamba, Ella Mae E Johann E Isagan, Abe Ernest Watkins, Maren Chicote, Meljune O Velarde, Michael C Villaraza, Aaron Joseph L Yu, Eizadora T Olivera, Baldomero M Concepcion, Gisela P Lluisma, Arturo O Animals Conotoxins Conus Snail Receptors, Nicotinic Mice Humans Cell Line, Tumor Peptides Nicotinic Antagonists Amino Acid Sequence Conusvenoms are composed of peptides that are commonly post-translationally modified, increasing their chemical diversity beyond what is encoded in the genome and enhancing their potency and selectivity. This study describes how PTMs alter an α-conotoxin's selectivity for specific nAChR subtypes. Venom from the cone snailConus(Asprella)neocostatuswas fractionated using high-performance liquid chromatography and tested using a behavioral intracranial mouse bioassay and a cholinergic calcium imaging assay using SH-SY5Y neuroblastoma cells. Four peptides were isolated from three HPLC fractions and found to have similar amino acid sequences using tandem mass spectrometry; they all containC-terminal amidation. The four peptides appear to be encoded by a single gene as indicated by transcriptomic analysis. One of these, NcIA, contains no additional PTM. NcIB lacked the two glycine residues found in the N-terminus of NcIA and contained two hydroxylated prolines. Analogs of both peptides containing a ɣ-carboxylated glutamic residue (NcIA[E15γ] and NcIB[E13γ]) were also isolated. Functional assays revealed distinct receptor selectivity: NcIA inhibited nicotine-evoked responses by over 70 %, while NcIA[E15γ] did not. Conversely, NcIB[E13γ] was inhibitory (∼60 %), but NcIB was not. Against choline-evoked responses, NcIA was weakly inhibitory (∼40 %), whereas the other three were nearly fully inhibitory. The ICvalues for NcIB and NcIB[E13γ] were 91.0 nM and 64.7 nM, respectively. These findings indicate that PTMs andN-terminal modifications influence peptide potency and receptor specificity, suggesting that cone snails use variable peptide processing not only to generate chemical diversity in their venom but also to fine-tune the pharmacology of its components. |
| format | Artículo científico |
| id | pubmed_39880316 |
| institution | PubMed |
| language | en |
| publishDate | 2025 |
| publisher | Biochemical pharmacology |
| record_format | pubmed |
| spellingShingle | Variable peptide processing of a Conus (Asprella) neocostatus α-conotoxin generates bioactive toxiforms that are potent against distinct nicotinic acetylcholine receptor subtypes. Ramones, Cydee Marie V Taguchi, Ryoichi S Gamba, Ella Mae E Johann E Isagan, Abe Ernest Watkins, Maren Chicote, Meljune O Velarde, Michael C Villaraza, Aaron Joseph L Yu, Eizadora T Olivera, Baldomero M Concepcion, Gisela P Lluisma, Arturo O Animals Conotoxins Conus Snail Receptors, Nicotinic Mice Humans Cell Line, Tumor Peptides Nicotinic Antagonists Amino Acid Sequence Variable peptide processing of a Conus (Asprella) neocostatus α-conotoxin generates bioactive toxiforms that are potent against distinct nicotinic acetylcholine receptor subtypes. Ramones, Cydee Marie V Taguchi, Ryoichi S Gamba, Ella Mae E Johann E Isagan, Abe Ernest Watkins, Maren Chicote, Meljune O Velarde, Michael C Villaraza, Aaron Joseph L Yu, Eizadora T Olivera, Baldomero M Concepcion, Gisela P Lluisma, Arturo O Animals Conotoxins Conus Snail Receptors, Nicotinic Mice Humans Cell Line, Tumor Peptides Nicotinic Antagonists Amino Acid Sequence Conusvenoms are composed of peptides that are commonly post-translationally modified, increasing their chemical diversity beyond what is encoded in the genome and enhancing their potency and selectivity. This study describes how PTMs alter an α-conotoxin's selectivity for specific nAChR subtypes. Venom from the cone snailConus(Asprella)neocostatuswas fractionated using high-performance liquid chromatography and tested using a behavioral intracranial mouse bioassay and a cholinergic calcium imaging assay using SH-SY5Y neuroblastoma cells. Four peptides were isolated from three HPLC fractions and found to have similar amino acid sequences using tandem mass spectrometry; they all containC-terminal amidation. The four peptides appear to be encoded by a single gene as indicated by transcriptomic analysis. One of these, NcIA, contains no additional PTM. NcIB lacked the two glycine residues found in the N-terminus of NcIA and contained two hydroxylated prolines. Analogs of both peptides containing a ɣ-carboxylated glutamic residue (NcIA[E15γ] and NcIB[E13γ]) were also isolated. Functional assays revealed distinct receptor selectivity: NcIA inhibited nicotine-evoked responses by over 70 %, while NcIA[E15γ] did not. Conversely, NcIB[E13γ] was inhibitory (∼60 %), but NcIB was not. Against choline-evoked responses, NcIA was weakly inhibitory (∼40 %), whereas the other three were nearly fully inhibitory. The ICvalues for NcIB and NcIB[E13γ] were 91.0 nM and 64.7 nM, respectively. These findings indicate that PTMs andN-terminal modifications influence peptide potency and receptor specificity, suggesting that cone snails use variable peptide processing not only to generate chemical diversity in their venom but also to fine-tune the pharmacology of its components. |
| title | Variable peptide processing of a Conus (Asprella) neocostatus α-conotoxin generates bioactive toxiforms that are potent against distinct nicotinic acetylcholine receptor subtypes. |
| topic | Animals Conotoxins Conus Snail Receptors, Nicotinic Mice Humans Cell Line, Tumor Peptides Nicotinic Antagonists Amino Acid Sequence |
| url | https://pubmed.ncbi.nlm.nih.gov/39880316/ |