Structure-function Analysis of α-conotoxin PeIA and the Inhibition of Rat α3β4 Nicotinic Acetylcholine Receptors

The α3β4 nicotinic acetylcholine receptor (nAChR) subtype is widely expressed by neurons of the peripheral nervous system including those of dorsal root ganglion (DRG). Characterizing α3β4 nAChRs pharmacologically has been hampered by the lack of selective ligands capable of distinguishing among closely related subtypes, particularly between α3β4 and α6β4. In an effort to remedy this situation, we conducted structure-activity studies on α-conotoxin PeIA in order to identify residues of the peptide that influenced the potency for α3β4 nAChRs. Select substitutions of positions known to be important for PeIA activity were made and the resulting analogs tested for their ability to inhibit acetylcholine-gated currents mediated by rat α3β4 nAChRs heterologously expressed in Xenopus oocytes. Several of these analogs showed favorable increases in potency. The results of these studies offer important insights into the interactions of ligands with α3β4 nAChRs, and may inform future experiments developing analogs of PeIA that selectively and potently interact with the α3β4 subtype. Presented at the 2018 ACCESS Symposium at the University of Utah.