Cynthia M. Czajkowski
330 Bascom Hall
500 Lincoln Dr
Madison, WI 53706-1314
Ph.D., State University of New York
Structure/function relationship in neurotransmitter receptors
The opening and closing of ligand-gated ion channels (LGICs), which lie in the membranes of nerve cells, regulate information flow throughout the brain. Members of the pentameric LGIC superfamily include nicotinic acetylcholine receptors (nAChR), serotonin-type-3 receptors, gamma-aminobutyric acid type A receptors (GABAR) and glycine receptors. Defects in these channels lead to a variety of neurological diseases and psychiatric disorders. A number of therapeutic drugs, including muscle relaxants, sedative-hypnotics, anti-convulsants, anxiolytics, intravenous and volatile anesthetics, anti-emetics, drugs for nicotine addiction and drugs to treat Alzheimer’s disease target these channels. For these receptors, binding of neurotransmitter in the extracellular ligand-binding domain triggers opening of an intrinsic ion channel more than 50A away in the transmembrane domain of the receptor. Although we know a fair amount about the structure of these receptors, the mechanisms by which the binding of neurotransmitter triggers channel opening and the binding of drugs modulate pLGIC function are relatively unknown.
The major focus of the lab is on understanding the function and structure of the GABAR. GABARs mediate the majority of inhibition in the brain and are modulated by a variety of clinically important drugs, such as benzodiazepines, barbiturates, neurosteroids, anesthetics and anti-convulsants. Furthermore, GABAR mutations have been linked to familial epilepsies, schizophrenia and autism.
Work in my lab is focused on understanding how GABARs and related pLGICs work. First, how does GABA binding trigger the opening of the chloride-selective pore? Second, how does the binding of different drugs such as benzodiazepines, anesthetics, neurosteroids and barbiturates modulate GABAAR function? Third, how do GABAAR defects alter receptor function and contribute to disease? Finally, how do neurons control the assembly, trafficking and cell surface expression of GABAARs? We are using an array of biochemical, biophysical and electrophysiological approaches including two-electrode voltage clamping and patch-clamping, voltage clamp fluorimetry, rapid-ligand application, disulfide trapping, cysteine cross-linking, structural modeling, protein over-expression and purification, and SDSL-EPR to advance our understanding of how neurotransmitter binding is linked to pLGIC activation and how drug binding is coupled to receptor modulation.
Our work is providing new insights into how neurotransmitters activate pLGICs and how allosteric drugs modulate their activity. A deeper understanding of how these channels work at a molecular level will improve our ability to predict the actions of drugs and ligands that act on these channels, design safer and more effective drugs, develop better therapeutic strategies, and understand the etiology of disease-causing mutations.
Areas of Expertise
- Membrane & Cellular Biophysics
- Structural Biology