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Ryan Hibbs

Research

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 have investigated how different receptor subtypes are built, how drugs like nicotine and neuromuscular blockers act upon them, and how they open and close channels through the cell membrane to allow ion passage.

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 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 the common architecture to select for anions and mainly mediate inhibitory signaling.

The structural projects on both nicotinic and GABAA receptors have allowed us 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 part of emerging fields. We are excited to contribute in this rapidly developing translational area.

We have also have been working on 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. This project area exemplifies how curiosity about fascinating animal behavior can give rise to mechanistic insights spanning from the atomic to circuit to animal behavior levels. 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 tuned through natural toxins and both clinically essential and illicit drugs.

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

Select Publications

Selected Peer-reviewed Publications

  • Allard CAH*, Kang G*, Kim JJ*, Valencia-Montoya WA, Hibbs RE#, Bellono NW#. Structural basis of sensory receptor evolution in octopus. Nature 2023 Apr;616(7956):373-377. PMID: 37045920
  • Kang G*, Allard CAH*, Valencia-Montoya WA*, van Giesen L, Kim JJ, Kilian PB, Bai X, Bellono NW#, Hibbs RE#. Sensory specializations drive octopus and squid behaviour. Nature. 2023 Apr;616(7956):378-383. PMID: 37045917
  • Zhu, S, Sridhar, A, Teng, J, Howard, RJ, Lindahl, E Hibbs, RE. “Structural and dynamic mechanisms of GABAA receptor modulators with opposing activities.” Nature Communications 2022 Aug 6;13(1):4582. PMID: 35933426
  • Noviello, C.M., Kreye, J., Teng, J., Pruss, H.# and Hibbs, R.E.# “Structural mechanisms of GABAA receptor autoimmune encephalitis.” Cell 2022 Jul 7;185(14):2469-2477.e13. PMID: 35803245
  • Rahman, M.M., Basta, T., Teng, J., Lee, M., Worrell, B.T., Stowell, M.H.B.# and Hibbs, R.E.# “Structural mechanism of muscle nicotinic receptor desensitization and block by curare.” Nature Structural & Molecular Biology 2022 Apr;29(4):386-394. PMID: 35301478. Selected for cover.
  • Noviello, C.M., Gharpure, A., Mukhtasimova, N., Cabuco, R., Baxter, L., Borek, D., Sine, S.M. and Hibbs, R.E. “Structure and gating mechanism of the α7 nicotinic acetylcholine receptor.” Cell 2021 184(8):2121-2134. PMID: 33735609.
  • Kim, J.J., Gharpure, A., Teng, J., Zhuang, Y., Howard, R.J., Zhu, S., Noviello, C.M., Walsh, R.M. Jr., Lindahl, E., Hibbs, R.E. “Shared structural mechanisms of general anesthetics and benzodiazepines.” Nature 2020 585(7824):303-308. PMID: 32879488.
  • Rahman, M.M., Teng, J., Worrell, B.T., Noviello, C.M., Lee, M., Karlin, A., Stowell, M.H.B.# and Hibbs, R.E.# “Structure of the native muscle-type nicotinic receptor and inhibition by snake venom toxins.” Neuron 2020 106(6):952-962. PMID: 32275860.
  • Gharpure, A., Teng, J., Zhuang, Y., Noviello, C.M., Walsh, R.M. Jr., Cabuco, R., Howard, R.J., Zaveri, N.T., Lindahl, E. and Hibbs, R.E. “Agonist selectivity and ion permeation in the α3β4 ganglionic nicotinic receptor.” Neuron 2019: 104(3)501-511. PMID: 31488329
  • Zhu, S., Noviello, C.M., Teng, J., Walsh, R.M. Jr., Kim, J.J. and Hibbs, R.E. “Structure of a human synaptic GABAA receptor.” Nature 2018: 559(7712):67-72. PMID: 29950725. Selected for cover.
  • Walsh, R.M. Jr.#, Roh S.H.#, Gharpure, A., Morales-Perez, C.L., Teng, J. and Hibbs, R.E. “Structural principles of distinct assemblies of the human α4β2 nicotinic receptor.” Nature 2018: 557(7704):261-265. PMID: 29720657. #Equal contribution.
  • Morales-Perez, C.L., Noviello, C.M. and Hibbs, R.E. “X-ray structure of the human α4β2 nicotinic acetylcholine receptor.” Nature 2016: 538(7625):411-415. PMID: 27698419.
  • Morales-Perez, C.L., Noviello, C.M. and Hibbs, R.E. “Manipulation of subunit stoichiometry in heteromeric membrane proteins.” Structure 2016: 24(5):797-805. PMID: 27041595.

Reviews/Editorials

  • Kim, J.J. and Hibbs, R.E. “Direct structural insights into GABAA receptor pharmacology.” TiBS, 2021 Jun;46(6):502-517. PMID: 33674151
  • Gharpure, A., Noviello, C.M., Hibbs, R.E. “Progress in Nicotinic Receptor Structural Biology.” Neuropharmacology 2020: Online ahead of print: Apr 7;171:108086. PMID: 32272141
  • Kim, J.J. and Hibbs, R.E. “Bridges between antimalarials and synaptic transmission.” Neuron 2019: 101(4)546-547. PMID: 30790532

Book Chapters

  • Rahman, M.M., Worrell, B.T., Stowell M.H.B., and Hibbs, R.E. “Purification of a native nicotinic receptor.” Methods in Enzymology. Volume 654: Ion Channels: Channel Chemical Biology, Engineering, and Physiological Function. Eds: Daniel L. Minor Jr. and Henry M. Colecraft. 2021 653:189-206.
  • Hibbs, R.E., Zambon, A. “Nicotine and agents acting at the neuromuscular junction and autonomic ganglia.” Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 13th Edition. Eds. Laurence Brunton, Randa Hilal-Dandan and Bjorn Knollman. McGraw-Hill Publishing, 2018.
  • Hibbs, R.E., Zambon, A. “Agents acting at the neuromuscular junction and autonomic ganglia.” Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th Edition. Eds. Laurence Brunton, Bruce Chabner and Bjorn Knollman. McGraw-Hill Publishing, 2011.

Biography

Ryan Hibbs grew up in Corvallis, Oregon, got his BA degree in Chemistry-Biochemistry at Whitman College, obtained his PhD in Biomedical Sciences / Pharmacology at UC San Diego, and did postdoctoral research at the Vollum Institute at Oregon Health & Science University. Before moving to UCSD in 2023, he was an Assistant and Associate Professor of Neuroscience and Biophysics at UT Southwestern Medical Center for 10 years, where he maintains an adjunct faculty position. His honors include the Roland Robbins PhD dissertation award, the Klingenstein-Simons and McKnight Scholar awards, the UCSD Outstanding Alumnus Award, and the Norman Hackerman Award in Chemical Research.

Ryan Hibbs