Molecular Mechanisms of Neurotransmitter-gated Ion Channels
The laboratory is broadly interested in the relationship between structure and function in neurotransmitter-gated ion channels, with special emphasis on the Cys-loop superfamily of synaptic receptor-channels. Our main tools are single-channel recording and analysis, 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. Linear free-energy relationships and the dynamics of the closed <--> open conformational change.
Gonzalez-Gutierrez G, Wang Y, Cymes GD, Tajkhorshid, E, and Grosman, C. 2017. Chasing the open-state structure of pentameric ligand-gated ion channels. Journal of General Physiology, 149:1119–1138.
Cymes GD 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.
Cymes GD 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.
Harpole TJ 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.
Papke D, 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.
Gonzalez-Gutierrez G, Cuello LG, Nair SK, 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.
Cymes GD and Grosman C. 2012. The unanticipated complexity of the selectivity-filter glutamates of nicotinic receptors. Nature Chemical Biology, 8:975–981.
Gonzalez-Gutierrez G, Lukk T, Agarwal V, Papke D, Nair SK, 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.
Cymes GD 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.
Cymes GD and Grosman C. 2011. Tunable pKa values and the basis of opposite charge selectivities in nicotinic-type receptors. Nature, 474:526–530.
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.
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.
Elenes S, Decker M, Cymes GD, 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, 133:151-169.
Cymes GD and Grosman C. 2008. Pore-opening mechanism of the nicotinic acetylcholine receptor evinced by proton transfer. Nature Structural and Molecular Biology 15:389-396.
Elenes S, Ni Y, Cymes GD, and Grosman C. 2006. Desensitization contributes to the synaptic response of gain-of-function mutants of the muscle nicotinic receptor. Journal of General Physiology 128:615-627.
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 127:703-717.
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 127:719-735.
Cymes GD, Ni Y, and Grosman C. 2005. Probing ion-channel pores one proton at a time. Nature 438:975-980.
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 42:14977-14987.