About

Claudio F. Grosman is a Professor and Head of the Department of Molecular and Integrative Physiology at the University of Illinois. He also holds a professorship in the Neuroscience Program. He earned his B.S./M.Sc. in 1991 and Ph.D. in 1996 from the University of Buenos Aires, Argentina, followed by postdoctoral research at the State University of New York at Buffalo from 1997 to 2002. His laboratory focuses on the molecular mechanisms of neurotransmitter-gated ion channels, with a particular emphasis on the superfamily of nicotinic receptors. Using single-channel and ensemble electrophysiology alongside protein-engineering techniques, his research aims to elucidate the relationship between structure and function in these ion channels. Key areas of investigation include the quantitative characterization of ligand binding kinetics in different channel states, understanding the kinetics of postsynaptic current decay under physiological and pathological conditions, exploring linear free-energy relationships in channel conformational changes, and studying the structure-electrostatics relationship of the pore domain. Throughout his career, Grosman has been recognized with several honors including the Faculty Excellence Award in 2015, the Richard and Margaret Romano Professorial Scholar title in 2014, the Outstanding Advisor Medical Scholars Program award in 2012, and the James E. Heath Award for Excellence in Teaching Physiology in 2012.

Research topics

• Biochemistry
• Biology
• Crystallography
• Biophysics
• Chemistry
• Neuroscience
• Endocrinology

Selected publications

• Characterizing the Ion-Conductive State of the α7-Nicotinic Acetylcholine Receptor via Single-Channel Measurements and Molecular Dynamics Simulations

  The Journal of Physical Chemistry B · 2026-02-06

  article

  in patch-clamp cell-attached recordings. These results identify the conformations most compatible with the physiological open state and underscore the importance of unrestrained MD, ligand stabilization, and extracellular-vestibule geometry in shaping α7-nAChR conduction.

  PublisherDOI

• GABA _A receptor gating imaged on the millisecond timescale

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-30 · 3 citations

  preprintOpen access

  Type-A γ-aminobutyric receptors (GABA A Rs) are fast pentameric ligand gated ion channels (pLGICs) 1–5 . Within a millisecond, saturating agonist concentrations trigger activity bursts consisting of high-frequency fluctuations between conductive and non-conductive states 6,7 . These can last for tens to hundreds of milliseconds until, stochastically, receptors adopt stable, long-lived, desensitised conformations 2,8,9 . This highly dynamic process, known as gating, controls transient passages of chloride ions across plasma membranes to enable neurotransmission and other fundamental processes in animal physiology 10–12 . The conformational transitions inside activity bursts, inferred from electrophysiology, have remained inaccessible to structural biology investigation. Here we describe the gating motions of three GABA A receptor variants imaged within the first 10 milliseconds of agonist application by cryogenic electron microscopy (cryo-EM) 13 . We illustrate how activation and desensitisation proceed through multiple asymmetric states, supported by major secondary, tertiary and quaternary structural rearrangements, and demonstrate that the same gating principles apply to both homomeric and heteromeric GABA A Rs. Furthermore, we show that cholesterol and phospholipids stabilise newly formed inter-subunit interfaces and obstruct channel pores in short-lived desensitised states, while phosphatidylinositol 4,5-bisphosphate (PIP 2 ) precludes the opening of both α1β3 and α1β3γ2 GABA A R channels. Our results provide a novel framework to interpret decades of electrophysiology observations and suggest a broadly applicable approach to investigate mechanistically the vast arrays of physiological and pharmacological modulators of GABA A Rs 5,14 and other fast neurotransmitter receptors 15,16 . Moreover, the subunit interfaces and lipid-binding pockets that form and disappear during GABA A R gating provide new opportunities to discover modulators with improved specificity and therapeutic properties. One sentence summary Single-particle cryo-EM was used to explore the dynamic conformational landscape of three human GABA A receptor variants within the first 10 milliseconds of interaction with their neurotransmitter agonists.

  PublisherOA PDFDOI

• BPS2025 - A critical role for interdomain distance in allosteric communication in pLGICs

  Biophysical Journal · 2025-02-01

  article
  PublisherDOI

• Characterizing the Ion-Conductive State of the <i>α</i> 7-Nicotinic Acetylcholine Receptor via Single-Channel Measurements and Molecular Dynamics Simulations

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-19 · 1 citations

  preprintOpen access

  The α7-nicotinic acetylcholine receptor (α7-nAChR) is a cation-selective member of the superfamily of Cys-loop receptors. Ubiquitously expressed throughout the body of vertebrate animals, this pentameric ligand-gated ion channel participates in a wide range of physiological phenomena - as diverse as synaptic transmission and the control of excessive inflammation - and is an attractive therapeutic target for novel ligands. Although notable efforts have been made to understand this receptor-channel in terms of function and structure, many questions remain unanswered despite the molecular simplicity of its homomeric assembly. Recent cryo-EM studies have provided atomic models of this channel in different conformations, thus enabling the application of atomistic molecular dynamics (MD) simulations to the study of cation conduction. We perform both single-channel patch-clamp recordings and MD simulations on the α7-nAChR. MD simulations of an α7-nAChR model (PDB ID 7KOX) reproduced the measured single-channel conductance and revealed Poissonian ion permeation, which we further modelled as a double-Poisson process incorporating inter-event delay times. We found that cations can enter the channel through lateral fenestrations in the extracellular domain although the probability of ions following this lateral pathway - rather than the axial one - is much lower than observed in simulations of other Cys-loop receptors. We also examined other atomic models (PDB ID 7EKT and 8V80) of the α7-nAChR proposed to represent partially open states of the channel and found them to be non-conductive. This study provides insight into how ions permeate through the pore of the α7-nAChR and offers a detailed analysis of an ion-conductive conformation likely to represent the physiological open state of this receptor-channel.

  PublisherOA PDFDOI

• Disentangling the mechanistic role of loop-C capping in Cys-loop receptor activation

  Nature Communications · 2025-11-23 · 1 citations

  articleOpen accessSenior author

  A comparison of atomic models of Cys-loop receptors reveals that the largest rearrangement upon agonist binding and gating is the contraction ("capping") of the neurotransmitter binding-site loop C. The capping of this loop has often been suggested to act as the mechanical link that couples the binding of extracellular ligands to the gating of the transmembrane pore. However, because binding and gating are inextricably linked, testing this idea experimentally has proved challenging. Here, we disentangle binding and gating using mutagenesis, chimeric constructs, and functional assays. Our results point to the notion that loop-C capping is not required for the pore of Cys-loop receptors to open/desensitize in response to agonist binding to the extracellular domain. Instead, the functional impact of this marked rearrangement seems to be confined to local changes at the level of the neurotransmitter-binding sites, such as the transition from the unliganded state to the low-affinity agonist-bound conformation and/or the transition from the latter to the high-affinity bound state.

  PublisherOA PDFDOI

• Molecular dynamics study of α7 nicotinic acetylcholine receptor

  Biophysical Journal · 2024-02-01

  article
  PublisherDOI

• Electrically silent mutants unravel the mechanism of binding−gating coupling in Cys-loop receptors

  Science Advances · 2024-11-27 · 5 citations

  articleOpen accessSenior authorCorresponding

  The transduction of extracellular chemical signals into intracellular events relies on the communication between neighboring domains of membrane receptors. In the particular case of Cys-loop receptor channels, five short stretches of amino acids, one per subunit, link the extracellular and transmembrane domains in such a way that the ion permeability of the latter and the affinity for neurotransmitters of the former become tied to each other. Here, using direct functional approaches, we set out to understand the molecular bases of this crucial interdependence through the characterization of total loss-of-current mutations at the interface between domains. Our results indicate that domain-domain proximity plays a previously unnoticed critical role inasmuch as inserting a single residue in each linker rendered the two domains independent of each other. In marked contrast, loss-of-current mutations that leave the linkers' length unaltered did not compromise the interdomain coupling, but rather, seemed to cause agonist-bound closed receptors to desensitize without appreciably opening.

  PublisherDOI

• Probing function in ligand-gated ion channels without measuring ion transport

  bioRxiv (Cold Spring Harbor Laboratory) · 2022-03-09

  preprintOpen accessSenior authorCorresponding

  ABSTRACT Although the functional properties of ion channels are most accurately assessed using electrophysiological approaches, a number of experimental situations call for alternative methods. Here, working on members of the pentameric ligand-gated ion-channel (pLGIC) superfamily, we focused on the practical implementation of, and the interpretation of results from, equilibrium-type ligand-binding assays. Ligand-binding studies of pLGICs are—by no means—new, but the lack of uniformity in published protocols, large disparities between the results obtained for a given parameter by different groups, and a general disregard for constraints placed on the experimental observations by simple theoretical considerations suggested that a thorough analysis of this classic technique was in order. To this end, we present a detailed practical and theoretical study of this type of assay using radiolabeled α-bungarotoxin, unlabeled small-molecule cholinergic ligands, the human homomeric α7-AChR, and extensive calculations in the framework of a realistic five-binding-site reaction scheme. Furthermore, we show examples of the practical application of this method to tackle two long-standing questions in the field: whether ligand-binding affinities are sensitive to binding-site occupancy, and whether mutations to amino-acid residues in the transmembrane domain can affect the channel’s affinities for ligands that bind to the extracellular domain.

  PublisherOA PDFDOI

• Probing function in ligand-gated ion channels without measuring ion transport

  The Journal of General Physiology · 2022-04-29 · 6 citations

  articleOpen accessSenior authorCorresponding

  Although the functional properties of ion channels are most accurately assessed using electrophysiological approaches, a number of experimental situations call for alternative methods. Here, working on members of the pentameric ligand-gated ion channel (pLGIC) superfamily, we focused on the practical implementation of, and the interpretation of results from, equilibrium-type ligand-binding assays. Ligand-binding studies of pLGICs are by no means new, but the lack of uniformity in published protocols, large disparities between the results obtained for a given parameter by different groups, and a general disregard for constraints placed on the experimental observations by simple theoretical considerations suggested that a thorough analysis of this classic technique was in order. To this end, we present a detailed practical and theoretical study of this type of assay using radiolabeled α-bungarotoxin, unlabeled small-molecule cholinergic ligands, the human homomeric α7-AChR, and extensive calculations in the framework of a realistic five-binding-site reaction scheme. Furthermore, we show examples of the practical application of this method to tackle two longstanding questions in the field: our results suggest that ligand-binding affinities are insensitive to binding-site occupancy and that mutations to amino-acid residues in the transmembrane domain are unlikely to affect the channel's affinities for ligands that bind to the extracellular domain.

  PublisherOA PDFDOI

• An experimental test of the nicotinic hypothesis of COVID-19

  Proceedings of the National Academy of Sciences · 2022-10-24 · 10 citations

  articleOpen accessSenior author

  The pathophysiological mechanisms underlying the constellation of symptoms that characterize COVID-19 are only incompletely understood. In an effort to fill these gaps, a “nicotinic hypothesis,” which posits that nicotinic acetylcholine receptors (AChRs) act as additional severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptors, has recently been put forth. A key feature of the proposal (with potential clinical ramifications) is the suggested competition between the virus’ spike protein and small-molecule cholinergic ligands for the receptor’s orthosteric binding sites. This notion is reminiscent of the well-established role of the muscle AChR during rabies virus infection. To address this hypothesis directly, we performed equilibrium-type ligand-binding competition assays using the homomeric human α7-AChR (expressed on intact cells) as the receptor, and radio-labeled α-bungarotoxin (α-BgTx) as the orthosteric-site competing ligand. We tested different SARS-CoV-2 spike protein peptides, the S1 domain, and the entire S1–S2 ectodomain, and found that none of them appreciably outcompete [ 125 I]-α-BgTx in a specific manner. Furthermore, patch-clamp recordings showed no clear effect of the S1 domain on α7-AChR–mediated currents. We conclude that the binding of the SARS-CoV-2 spike protein to the human α7-AChR’s orthosteric sites—and thus, its competition with ACh, choline, or nicotine—is unlikely to be a relevant aspect of this complex disease.

  PublisherOA PDFDOI

Recent grants

• NIH Grant T32GM008276

  NIH · $7.0M · 2015

• NIH Grant R56NS042169

  NIH · $378k · 2008

• Mechanisms of Neurotransmitter-Gated Ion Channels

  NIH · $6.6M · 2003–2024

Frequent coauthors

• Giovanni González-Gutiérrez

  Indiana University Bloomington

  29 shared

• Gisela D. Cymes

  University of Illinois Urbana-Champaign

  23 shared

• Satish K. Nair

  University of Illinois Urbana-Champaign

  12 shared

• David Papke

  Brigham and Women's Hospital

  11 shared

• Tyler J. Harpole

  Quantitative BioSciences

  8 shared

• Anthony Auerbach

  University at Buffalo, State University of New York

  7 shared

• Vinayak Agarwal

  IIT@MIT

  6 shared

• Luis G. Cuello

  Texas Tech University Health Sciences Center

  6 shared

Education

• PhD, Biophysics

  University of Buenos Aires

Awards & 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 Physiol…