Contact Information
Research Interests
Research Topics
Ion Channels, Membrane Biology, Neurobiology, Protein Dynamics, Protein Structure, Receptor Biochemistry
Disease Research Interests
Neurological and Behavioral Disorders
Research Description
Molecular Mechanisms of Neurotransmitter-gated Ion Channels
My laboratory is broadly interested in the relationship between structure and function in neurotransmitter-gated ion channels, with special emphasis on the superfamily of nicotinic receptors. Our main tools are single-channel and ensemble electrophysiology, and protein-engineering techniques.
Some of the particular issues we have been working on lately are:
- Quantitative characterization of fundamental properties of neurotransmitter-gated ion channels such as rate and equilibrium constants of ligand binding in the closed and open states.
- Quantitative understanding of the different phenomena that contribute to the kinetics of the postsynaptic current decay under physiological and pathological conditions.
- Linear free-energy relationships and the chemical dynamics of the closed-to-open conformational change.
- Relationship between structure and electrostatics of the pore domain.
Education
B.S./M.Sc. 1991 University of Buenos Aires (Argentina)
Ph.D. 1996 University of Buenos Aires (Argentina)
Postdoc. 1997-2002 State University of New York at Buffalo
Awards and Honors
2015 Faculty Excellence Award
2014 Richard and Margaret Romano Professorial Scholar
2012 Outstanding Advisor Medical Scholars Program
2012 James E. Heath Award for Excellence in Teaching Physiology
Additional Campus Affiliations
External Links
Highlighted Publications
Representative Publications
Godellas, N.E., Cymes, G.D., and Grosman, C. 2024. Electrically silent mutants unravel the mechanism of binding–gating coupling in Cys-loop receptors. Science Advances, 10, eadq8048. [Abstract]
Godellas, N.E., Cymes, G.D., and Grosman, C. 2022. An experimental test of the nicotinic hypothesis of COVID-19. PNAS, 119: e2204242119. [Abstract]
Godellas, N.E., and Grosman, C. 2022. Probing function in ligand-gated ion channels without measuring ion transport. Journal of General Physiology, 154: e202213082.[Abstract] [Commentary]
Kumar, P., Cymes, G.D., and Grosman, C. 2021. Structure and function at the lipid–protein interface of a pentameric ligand-gated ion channel. PNAS, 118: e2100164118.[Abstract]
Cymes, G.D., and Grosman, C. 2021. Signal transduction through Cys-loop receptors is mediated by the nonspecific bumping of closely apposed domains. PNAS, 118:e2021016118. [Abstract]
Sethuramanujam, S., Matsumoto, A., deRosenroll, G., Murphy-Baum, B., Grosman, C., McIntosh, J.M., Jing, M., Li, Y., Berson, D., Yonehara, K., Awatramani, G.B. 2021. Rapid multi-directed cholinergic transmission in the central nervous system. Nature Communications, 12:1374. [Abstract]
Kumar, P., Wang, Y., Zhang, Z., Zhao, Z., Cymes, G.D., Tajkhorshid, E., and Grosman, C. 2019. Cryo-EM structures of a lipid-sensitive pentameric ligand-gated ion channel embedded in a phosphatidylcholine-only bilayer. PNAS, 117:1788–1798. [Abstract]
Harpole, T. J. and Grosman, C. 2019. A crucial role for side-chain conformation in the versatile charge selectivity of Cys-loop receptors. Biophysical Journal, 116:1667–1681. [Abstract]
Gonzalez-Gutierrez, G., Wang, Y., Cymes, G.D., Tajkhorshid, E., and Grosman, C. 2017. Chasing the open-state structure of pentameric ligand-gated ion channels. Journal of General Physiology, 149:1119–1138. [Abstract]
Cymes, G. D. and Grosman, C. 2016. Identifying the elusive link between amino acid sequence and charge selectivity in pentameric ligand-gated ion channels. PNAS, 113:E7106–E7115. [Abstract] [Commentary][
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Cymes, G. D. and Grosman, C. 2015. Engineered Ionizable Side Chains. In Novel Chemical Tools to Study Ion Channel Biology. Ch. 2. Springer, New York. C. Ahern and S. Pless Eds.
Gonzalez-Gutierrez, G. and Grosman, C. 2015. The atypical cation-conduction and gating properties of ELIC underscore the marked functional versatility of the pentameric ligand-gated ion-channel fold. Journal of General Physiology, 146:15–36. [Abstract]
Harpole, T. J. and Grosman, C. 2014. Side-chain conformation at the selectivity filter shapes the permeation free-energy landscape of an ion channel. PNAS, 111:E3196–E3205 [Abstract]
Papke, D. and Grosman, C. 2014. The role of intracellular linkers in gating and desensitization of human pentameric ligand-gated ion channels. Journal of Neuroscience, 34:7238–7252. [Abstract]
Gonzalez-Gutierrez, G., Cuello, L. G., Nair, S. K. and Grosman, C. 2013. Gating of the proton-gated ion channel from Gloeobacter violaceus at pH 4 as revealed by X-ray crystallography. PNAS, 110:18716–18721. [Abstract]
Cymes, G. D. and Grosman, C. 2012. The unanticipated complexity of the selectivity-filter glutamates of nicotinic receptors. Nature Chemical Biology, 8:975–981. [Abstract][News and Views]
Gonzalez-Gutierrez, G., Lukk, T., Agarwal, V., Papke, D., Nair, S. K. and Grosman, C. 2012. Mutations that stabilize the open state of the Erwinia chrisanthemi ligand-gated ion channel fail to change the conformation of the pore domain in crystals. PNAS, 109:6331–6336. [Abstract]
Cymes, G. D. and Grosman, C. 2011. Estimating the pKa values of basic and acidic side chains in ion channels using electrophysiological recordings: a robust approach to an elusive problem. Proteins, 79:3485–3493. [Abstract]
Cymes, G. D. and Grosman, C. 2011. Tunable pKa values and the basis of opposite charge selectivities in nicotinic-type receptors. Nature, 474:526–530. [Abstract]
Papke, D., Gonzalez-Gutierrez, G. and Grosman, C. 2011. Desensitization of neurotransmitter-gated ion channels during high-frequency stimulation: a comparative study of Cys-loop, AMPA and purinergic receptors. Journal of Physiology, 589:1571–1585. [Abstract]
Gonzalez-Gutierrez, G. and Grosman, C. 2010. Bridging the gap between structural models of nicotinic receptor superfamily ion channels and their corresponding functional states. Journal of Molecular Biology, 403:693–705. [Abstract]
Elenes, S., Decker, M., Cymes, G. D. and Grosman, C. 2009. Decremental response to high-frequency trains of acetylcholine pulses but unaltered fractional Ca2+ currents in a panel of "slow-channel syndrome" nicotinic receptor mutants. Journal of General Physiology, 133:151–69. [Abstract]
Cymes, G. D. and Grosman, C. 2008. Pore-opening mechanism of the nicotinic acetylcholine receptor evinced by proton transfer. Nature Structural and Molecular Biology, 15(4):389–96. [Abstract]
Elenes, S., Ni, Y., Cymes, G.D. and Grosman, C. 2006. Desensitization contributes to the synaptic response of gain-of-function mutants of the muscle nicotinic receptor. Journal of General Physiology, 128:615–27. [Abstract]
Purohit, Y. and Grosman, C. 2006. Block of muscle nicotinic receptors by choline suggests that the activation and desensitization gates act as distinct molecular entities. Journal of General Physiology 127:703–17. [Abstract]
Purohit, Y. and Grosman, C. 2006. Estimating binding affinities of the nicotinic receptor for low-efficacy ligands using mixtures of agonists and two-dimensional concentration-response relationships. Journal of General Physiology, 127:719–35. [Abstract]
Cymes, G.D., Ni, Y. and Grosman, C. 2005. Probing ion-channel pores one proton at a time. Nature, 438:975–80. [Abstract] [News and Views][]
Grosman, C. 2003. Free-energy landscapes of ion-channel gating are malleable: changes in the number of bound ligands are accompanied by changes in the location of the transition state in acetylcholine receptor channels. Biochemistry, 42:14977–87. [Abstract]
Grosman, C. 2002. Linear Free-Energy Relationships and the Dynamics of Gating in the Acetylcholine Receptor Channel. A phi-value analysis of an allosteric transition at the single-molecule level. Journal of Biological Physics, 28:267–77. [Article]
Recent Publications
Godellas, N. E., Cymes, G. D., & Grosman, C. (2024). Electrically silent mutants unravel the mechanism of binding−gating coupling in Cys-loop receptors. Science Advances, 10(48), Article eadq8048. https://doi.org/10.1126/sciadv.adq8048
Godellas, N. E., Cymes, G. D., & Grosman, C. (2022). An experimental test of the nicotinic hypothesis of COVID-19. Proceedings of the National Academy of Sciences of the United States of America, 119(44), Article e2204242119. https://doi.org/10.1073/pnas.2204242119
Godellas, N. E., & Grosman, C. (2022). Probing function in ligand-gated ion channels without measuring ion transport. Journal of General Physiology, 154(6), Article e202213082. https://doi.org/10.1085/jgp.202213082
Cymes, G. D., & Grosman, C. (2021). Signal transduction through Cys-loop receptors is mediated by the nonspecific bumping of closely apposed domains. Proceedings of the National Academy of Sciences of the United States of America, 118(14), Article e2021016118. https://doi.org/10.1073/pnas.2021016118
Kumar, P., Cymes, G. D., & Grosman, C. (2021). Structure and function at the lipid-protein interface of a pentameric ligand-gated ion channel. Proceedings of the National Academy of Sciences of the United States of America, 118(23), Article e2100164118. https://doi.org/10.1073/pnas.2100164118
