Stoichiometry dependent inhibition of rat α3β4 nicotinic acetylcholine receptor by the ribbon isomer of α-conotoxin AuIB

Biochemical Pharmacology
Xiaosa WuQuentin Kaas

Abstract

The ribbon isomer of α-conotoxin AuIB has 10-fold greater potency than the wild-type globular isomer at inhibiting nicotinic acetylcholine receptors (nAChRs) in rat parasympathetic neurons, and unlike its globular isoform, ribbon AuIB only targets a specific stoichiometry of the α3β4 nAChR subtype. Previous electrophysiological recordings of AuIB indicated that ribbon AuIB binds to the α3(+)α3(-) interface within the nAChR extracellular domain, which is displayed by the (α3)3(β4)2 stoichiometry but not by (α3)2(β4)3. This specificity for a particular stoichiometry is remarkable and suggests that ribbon isoforms of α-conotoxins might have great potential in drug design. In this study, we investigated the binding mode and structure-activity relationships of ribbon AuIB using a combination of molecular modeling and electrophysiology recording to determine the features that underpin its selectivity. An alanine scan showed that positions 4 and 9 of ribbon AuIB are the main determinants of the interaction with (α3)3(β4)2 nAChR. Our computational models indicate that the first loop of ribbon AuIB binds in the "aromatic box" of the acetylcholine orthosteric binding site, similar to that of globular AuIB. In contrast, the second loop an...Continue Reading

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