Research

Ion channels in the nervous system: structure, biophysics, pharmacology, disease, and evolution

We are broadly interested in how ion channels enable fast signaling across membranes. This signaling underlies diverse physiological processes, from chemical transmission in the brain, to muscle contraction, to environmental sensation. Our projects usually build from studying the structure of an ion channel as a foundation for understanding how it works. We have used X-ray crystallography and more recently cryo-electron microscopy to probe the 3D structure of a family of neurotransmitter receptors. This new structural information is a launching pad for diverse experiments to study, often collaboratively, the receptor dynamics, how the receptors are regulated by drugs, how they evolve to play different signaling roles, and how their normal signaling is disrupted in disease. 

One branch of the lab focuses on nicotinic acetylcholine receptors, which mediate millisecond timescale signaling between neurons and between motor neurons and muscle. Receptors in this family also play important but poorly understood roles in the immune system. We discovered how different receptor subtypes are built, how drugs like nicotine and neuromuscular blockers act upon them, how they open and close channels through the cell membrane to allow ion passage, and how replacement of subunits enables development of neuromuscular junctions and muscle contraction.

Another branch of the lab studies GABAA receptors, which are found at roughly a third of the connections between neurons in the brain. Effort on these receptors has focused on general protein structure and on how general anesthetics, anxiolytics, sedative-hypnotics, and drugs of abuse act on them. GABAA receptors share the same pentameric architecture as nicotinic receptors, but rather than being excitatory cation channels, they have instead adapted this architecture to select for anions and mainly mediate inhibitory signaling.

The structural projects on both nicotinic and GABAA receptors laid a foundation to study several autoimmune diseases involving these proteins. Antibodies that are inappropriately produced against one’s own nicotinic receptors and GABAA receptors can cause diseases including GABAA encephalitis, myasthenia gravis, and autoimmune autonomic disorders. How these diseases originate, how the antibodies cause the disease, and how to treat them, are patient specific, and are parts of emerging fields, with the first autoantibodies against neuronal receptors only discovered in 2006. We are excited to contribute in this rapidly developing translational area.

In a neuroethology project, we have been studying a distantly related branch of this same neurotransmitter receptor superfamily found in cephalopods like octopus, cuttlefish, and squid. These marine animals have adapted the same pentameric ion channel architecture to mediate sensation of environmental molecules, using receptors on the surface of their arm suckers.

Together, these projects teach us about how the ion channels are built, how they work to mediate fast signaling in the brain and body, and how their activity can be altered by autoimmune antibodies, natural toxins, and both clinically essential and illicit drugs.

Many of our projects have been supported or driven by fantastic collaborators, including Kevin O'Connor (Yale), Steven Sine (Mayo Clinic), Michael Stowell (CU Boulder), Erik Lindahl (University of Stockholm), Nick Bellono (Harvard), Michael McIntosh (University of Utah), Harald Prüss (DZNE Berlin), Marco Cecchini (Strasbourg) and Steven Vernino and Nancy Monson (UT Southwestern).