Tuning the allosteric regulation of artificial muscarinic and dopaminergic ligand-gated potassium channels by protein engineering of G protein-coupled receptors

Christophe J. Moreau, Jean Revilloud, Lydia N. Caro, Julien P. Dupuis, Amandine Trouchet, Argel Estrada-Mondragón, Katarzyna Nieścierowicz, Nicolas Sapay, Serge Crouzy, Michel Vivaudou
Sci Rep. 2017-02-01; 7(1):
DOI: 10.1038/srep41154

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Ligand-gated ion channels enable intercellular transmission of action potential
through synapses by transducing biochemical messengers into electrical signal. We
designed artificial ligand-gated ion channels by coupling G protein-coupled
receptors to the Kir6.2 potassium channel. These artificial channels called ion
channel-coupled receptors offer complementary properties to natural channels by
extending the repertoire of ligands to those recognized by the fused receptors,
by generating more sustained signals and by conferring potassium selectivity. The
first artificial channels based on the muscarinic M2 and the dopaminergic D2L
receptors were opened and closed by acetylcholine and dopamine, respectively. We
find here that this opposite regulation of the gating is linked to the length of
the receptor C-termini, and that C-terminus engineering can precisely control the
extent and direction of ligand gating. These findings establish the design rules
to produce customized ligand-gated channels for synthetic biology applications.

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