Optochemical control of genetically engineered neuronal nicotinic acetylcholine receptors

Ivan Tochitsky , Matthew R. Banghart , Alexandre Mourot (1) , Jennifer Z. Yao , Benjamin Gaub , Richard H. Kramer , Dirk Trauner

1 NPS-06 - Neurophysiologie et comportements = Neurophysiology and Behavior

Advances in synthetic chemistry, structural biology, molecular modelling and molecular cloning have enabled the systematic functional manipulation of transmembrane proteins. By combining genetically manipulated proteins with light-sensitive ligands, innately `blind' neurobiological receptors can be converted into photoreceptors, which allows them to be photoregulated with high spatiotemporal precision. Here, we present the optochemical control of neuronal nicotinic acetylcholine receptors (nAChRs) with photoswitchable tethered agonists and antagonists. Using structure-based design, we produced heteromeric alpha 3 beta 4 and alpha 4 beta 2 nAChRs that can be activated or inhibited with deep-violet light, but respond normally to acetylcholine in the dark. The generation of these engineered receptors should facilitate investigation of the physiological and pathological functions of neuronal nAChRs and open a general pathway to photosensitizing pentameric ligand-gated ion channels.

Domaines: Neurosciences [q-bio.NC]

Ivan Tochitsky, Matthew R. Banghart, Alexandre Mourot, Jennifer Z. Yao, Benjamin Gaub, et al.. Optochemical control of genetically engineered neuronal nicotinic acetylcholine receptors. Nature Chemistry, 2012, 4 (2), pp.105-111. ⟨10.1038/NCHEM.1234⟩. ⟨hal-01542264⟩