Nicotinic acetylcholine receptor structural pharmacology and gating transitions.

Abstract

Our lab focuses on using structural and functional approaches to understand signaling by ligand-gated ion channels in the nervous system. A major emphasis is on understanding nicotinic receptor pharmacology from a structural perspective. Here I will present some of our recent work using the muscle-type nicotinic receptor from the Torpedo ray as a structurally tractable reference for the human receptor at the neuromuscular junction. I will focus on how toxins from animals and plants, as well as drugs used in the clinic, act on the receptor, and how we can use this information to understand state transitions that underlie ion channel gating. These studies have revealed a new class of allosteric site at the junction of the extracellular and transmembrane domains that small molecules can leverage to modulate channel desensitization. Our findings suggest that stabilizing a desensitized-like non-conducting state, through this allosteric site, is an important alternative mechanism for antagonizing the receptor.