Molecular Mechanisms Underlying Glycinergic Neurotransmission
DeWitt Stetten Jr. Lecture | to
Sudha Chakrapani, Ph.D.
Joseph T. Wearn, MD University Professor in Medicine
Director, Cryo-Electron Microscopy Core
Director, Cleveland Center for Membrane and Structural Biology
Case Western Reserve University, School of Medicine
Born and raised in India, Dr. Sudha Chakrapani came to the United States after completing her master’s degree in biomedical engineering. She received her Ph.D. in physiology and biophysics from the University at Buffalo and went on to complete postdoctoral positions at the University of Virginia and the University of Chicago. In 2010, she joined the faculty at Case Western Reserve University in Cleveland, Ohio, in the department of physiology and biophysics. She is now a professor and chair of the department of pharmacology and serves as the director of the Cleveland Center for Membrane and Structural Biology.
Over the last 25 years, Dr. Chakrapani’s research has focused on ion channels that mediate fast synaptic transmission at the neuronal and neuromuscular junction. She is especially interested in understanding the critical interaction between ion channels and bioactive lipids, including how this interaction is altered in the presence of different molecules like neurosteroids, alcohols, and anesthetics. Her lab’s scientific approach combines cutting-edge multidisciplinary tools that include cryo-electron microscopy (Cryo-EM) and X-ray crystallography for high-resolution structure determination, electron paramagnetic resonance (EPR) spectroscopy for protein dynamic measurements, and electrophysiology for functional characterization of ion channels. These techniques complement each other and provide an atomic description of how structure and dynamics govern protein functioning.
Dr. Chakrapani is supported by the NIGMS Maximizing Investigators’ Research Award program through grant R35GM134896.
Summary
Glycine Receptors (GlyRs) at the inhibitory synapses in the spinal cord and brainstem are key players in regulating motor and sensory signals. Differential expression of GlyR subtype governs their widely differing physiological functions, ranging from muscle tone and respiratory rhythm to pain perception. GlyR dysfunctions are associated with epilepsy, chronic pain, addiction, and autism. Targeted regulation of specific GlyR subtypes will require a detailed understanding of their structure, function, and pharmacology. Using cryogenic electron microscopy, electrophysiology, and molecular dynamic simulations, we have uncovered fundamental mechanisms that underlie GlyR activation by glycine and modulation by various endogenous and exogenous ligands. Molecular insights into these regulatory pathways pave the way for subtype-specific drug development.
Learning Objectives:
- To appreciate the diverse roles played by various glycine receptor subtypes in normal physiology and disease states
- To learn about the structural details of GlyR assembly and the mechanisms that govern their function and drug modulation.
https://videocast.nih.gov/watch=55010
This page was last updated on Thursday, November 14, 2024