aS-conotoxin GVIIIB potently and selectively blocks a9a10 nicotinic XXXX receptors.

@entity5376 @entity462 @entity35 @entity393 @entity934
UNASSIGNED: Although @entity934 is widely utilized in vertebrate nervous systems, nicotinic @entity934 receptors (nAChRs), including the a9a10 subtype, also are expressed in a wide variety of non-neuronal cells. These cell types include cochlear hair cells, adrenal chromaffin cells and immune cells. a9 @entity35 nAChRs present in these cells may respectively play roles in protection from noise-induced @entity393 , response to stress and neuroprotection. Despite these critical functions, there are few available selective ligands to confirm mechanistic hypothesis regarding the role of a9a10 nAChRs. Conus, has been a rich source of ligands for receptors and ion channels. Here, we identified Conus geographus venom as a lead source for a novel a9a10 antagonist. The active component was isolated and the encoding gene cloned. The peptide signal sequence and @entity462 arrangement had the signature of the   -conotoxin superfamily. Previously isolated   -conotoxin GVIIIA, also from Conus geographus, targets the @entity5376 . In contrast, aS-GVIIIB blocked the a9a10 nAChR with an IC50 of 9.8nM, yet was inactive at the @entity5376 . Pharmacological characterization of aS-GVIIIB shows that it is over 100-fold selective for the a9a10 nAChR compared to other nAChR subtypes. Thus, the S-superfamily represents a novel conotoxin scaffold for flexibly targeting a variety of receptor subtypes. Functional competition studies utilized distinct off-rate kinetics of conotoxins to identify the a10/a9 nAChR interface as the site of aS-GVIIIB binding; this adds to the importance of the (+) face of the a10 rather than the (+) face of the a9 nAChR subunit as critical to binding of a9a10-targeted conotoxins.
