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Analogs of α-conotoxin MII are selective for α6-containing nicotinic acetylcholine receptors

Neuronal nicotinic acetylcholine receptors (nAChRs) both mediate direct cholinergic synaptic transmission and modulate synaptic transmission by other neurotransmitters. Novel ligands are needed as probes to discriminate among structurally related nAChR subtypes. α-Conotoxin MII, a selective ligand that discriminates among a variety of nAChR subtypes, fails to discriminate well between some subtypes containing the closely related α3 and α6 subunits. Structure-function analysis of α-conotoxin MII was performed in an attempt to generate analogs with preference for α6-containing [α6* (asterisks indicate the possible presence of additional subunits)] nAChRs. Alanine substitution resulted in several analogs with decreased activity at α3* versus α6* nAChRs heterologously expressed in Xenopus laevis oocytes. From the initial analogs, a series of mutations with two alanine substitutions was synthesized. Substitution at His9 and Leu15 (MII[H9A;L15A]) resulted in a 29-fold lower IC50 at α6β4 versus α3β4 nAChRs. The peptide had a 590-fold lower IC50 for α6/α3β2 versus α3β2 and a 2020-fold lower IC50 for α6/α3β2β3 versus α3β2 nAChRs. MII[H9A;L15A] had little or no activity at α2β2, α2β4, α3β4, α4β2, α4β4, and α7 nAChRs. Functional block by MII[H9A;L15A] of rat α6/α3β2β3 nAChRs (IC50 = 2.4 nM) correlated well with the inhibition constant of MII[H9A;L15A] for [125I]α-conotoxin MII binding to putative α6β2* nAChRs in mouse brain homogenates ( K i = 3.3 nM). Thus, structure-function analysis of α-conotoxin MII enabled the creation of novel selective antagonists for discriminating among nAChRs containing α3 and α6 subunits.