Back to the future: Rational maps for exploring acetylcholine receptor space and time

Global functions of nicotinic acetylcholine receptors, such as subunit cooperativity and compatibility, likely emerge from a network of amino acid residues distributed across the entire pentameric complex. Identification of such networks has stymied traditional approaches to acetylcholine receptor structure and function, likely due to the cryptic interdependency of their underlying amino acid residues. An emerging evolutionary biochemistry approach, which traces the evolutionary history of acetylcholine receptor subunits, allows for rational mapping of acetylcholine receptor sequence space, and offers new hope for uncovering the amino acid origins of these enigmatic properties. •Molecular phylogenies rationally map acetylcholine receptor sequence space.•Ancestral acetylcholine receptor subunits represent molecular transitional forms.•Hybrid acetylcholine receptors incorporating ancestral subunits are viable.