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Science 333 (6047): 1292-1296

Copyright © 2011 by the American Association for the Advancement of Science

Chemical and Genetic Engineering of Selective Ion Channel–Ligand Interactions

Christopher J. Magnus,* Peter H. Lee,* Deniz Atasoy,* Helen H. Su, Loren L. Looger, Scott M. Sternson{dagger}

Abstract: Ionic flux mediates essential physiological and behavioral functions in defined cell populations. Cell type–specific activators of diverse ionic conductances are needed for probing these effects. We combined chemistry and protein engineering to enable the systematic creation of a toolbox of ligand-gated ion channels (LGICs) with orthogonal pharmacologic selectivity and divergent functional properties. The LGICs and their small-molecule effectors were able to activate a range of ionic conductances in genetically specified cell types. LGICs constructed for neuronal perturbation could be used to selectively manipulate neuron activity in mammalian brains in vivo. The diversity of ion channel tools accessible from this approach will be useful for examining the relationship between neuronal activity and animal behavior, as well as for cell biological and physiological applications requiring chemical control of ion conductance.

Janelia Farm Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA 20147, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: sternsons{at}janelia.hhmi.org


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