Regulation & Desensitization of Ligand-Gated Ion Channels

Pentameric ligand-gated channels mediate signals across the kingdoms of life, and are highly sensitive to modulators such as benzodiazepines, anesthetics or alcohol.

Recent advances in cryo-EM have enabled us to identify and obtain structures of several new channels, including new prokaryotic model system and heteromeric channels in the human nervous system.

We seek to use this to determine the molecular mechanisms of the gating process, explain subtype-specific binding and modulation for human channels, and understand why channels spontaneously desensitize shortly after opening.

In particular, we propose to use cryo-EM, molecular dynamics simulations, and neutron scattering to understand gating and regulation by pH and calcium for a new symbiote multi-domain channel (DeCLIC) that shares many properties with human channels.

We will also use simulations and electrophysiology to quantify modulator binding in specific subtype interfaces of our recently reported cryo-EM structures of a human heteromeric GABA(A) receptor, and pursue a structure of a new GABA(A) subtype showing tissue-specific modulation by neurosteroids.

Finally, we will use new acetylcholine receptor structures to describe the mechanism of the entire cycle through open-closed-desensitized states.

This should advance our fundamental understanding of conformational transitions for a broad class of physiologically important ligand-gated channels, and particularly shed light on subtype-specific drug (side-)effects.