The nicotinic acetylcholine receptors are a family of excitatory pentameric ligand-gated ion channels. They have a conserved gating cycle that tightly regulates ion flow. In the absence of agonist, the channel adopts a closed-resting state. Agonist binding drives the channel into an activated, ion-conducting conformation. Then, in the sustained presence of agonist, the channel transitions into a non-conducting, desensitized state. Previous work toward this project resulted in the first structures of neuronal nicotinic receptors and in structures of the muscle-type and homomeric α7 nicotinic receptors in multiple gating cycle conformations. Future work is focused on expanding our current knowledge of the gating cycle and investigating how small molecules target nicotinic receptors and modulate channel gating. Contributed by PhD student Sean Burke, Hibbs lab.

These ligand-gated ion channels are best known for their roles in mediated fast inhibitory signaling in the brain. Activating these receptors results in opening an intrinsic anion channel, permeable to chloride, the most abundant biological anion. Because the membrane potential at which chloride is at equilibrium is near the resting membrane potential in most neurons, opening of a GABAA receptor tends to oppose neuronal excitability. Dysfunction of GABAA receptors results in diseases of hyperexcitability including seizure disorders. Many therapeutic and illicit compounds target GABAA receptors. We aim to understand where these drugs bind to the receptor, and how their binding affects the ability of the neurotransmitter GABA to activate the channel. Image by PhD Student Weronika Chojnacka, Hibbs lab.

Ion channels in the Cys-loop receptor superfamily are critical to such broad processes as neuronal excitation and inhibition, muscle contraction, and inflammation. Autoantibodies against family members are associated with myasthenia gravis, which causes intermittent muscle weakness and fatigue. More autoantibodies are now being discovered targeting other family members and can cause illnesses such as autoimmune encephalitis or dysautonomia. We are studying these diseases from a structural standpoint; we partner with clinicians and immunologists to isolate antibodies from patients and then obtain structures of these autoantibodies in complex with their physiological targets. We expand on the structures with electrophysiology and other cell-based assays to discover how the antibodies cause disease. This project is led by Assistant Professor Colleen Noviello, who brings a background in immunology and infectious disease. Art by Lab Manager Leah Baxter, Hibbs lab.

While pentameric ligand-gated ion channels allow for fast communication between cells in humans, this receptor family has been leveraged by cephalopods, like octopus, squid, and cuttlefish, for sensing of their marine environment. Chemotactile receptors present on these creatures’ sucker pads sense diverse molecules to regulate predatory behavior. Nick Bellono’s lab at Harvard discovered this family of channels. We have been working with them to define the structural adaptions of a common receptor architecture toward a very different purpose. Photo credit, Anik Grearson @ Harvard University. Cryo-EM structures by Postdoctoral Fellow Guipeun Kang, Hibbs lab.