| Description |
Nicotinic acetylcholine receptors (nAChRs) are a class of ligand gated ion channels that are widely distributed in neuronal and non-neuronal cell types. One subtype of nAChRs, the α9α10 nAChR, is of particular interest as it has been implicated in pain signaling. Block of the α9α10 nAChR has demonstrated analgesia in several animal models. Because of the role of these receptors in pain, the discovery of antagonists of the α9α10 nAChR has important practical applications. Conus is a genus of venomous mollusks whose venom components have been widely utilized as pharmacological tools to discriminate between receptor and ion channel subtypes. Several species of Conus were selected and screened for activity against the α9α10 nAChR, with two of the venoms selected for further study. Subsequent purification led to the discovery of αS-GVIIIB, a novel σ-conotoxin that is potent for the α9α10 nAChR with an IC50 of 9.8 nM, and is over 100-fold more selective for the α9α10 nAChR compared to other nAChR subtypes. Furthermore, αS-GVIIIB gives increased insight into the σ-conotoxin family, a class of toxins that is not widely studied. Of particular interest is that the previously discovered σ-GVIIIA is selective for the 5-HT3 serotonin receptor and the newly discovered αS-GVIIIB, from the same Conus species, targets a different class of ligand-gated ion channels. The understanding of σ-conotoxins was also furthered with the demonstration that αS-GVIIIB competes with α-RgIA for the ACh binding domain, illustrating that αS-GVIIIB is a competitive antagonist. Also, toxins from the αD-conotoxin family are potent for the α9α10 nAChR, but selectivity is not a key feature as the αD-conotoxins are also potent for several other nAChRs. |
