Cynthia M. Czajkowski

Professor
Ph.D., 1987, State University of New York

Contact Information
Email: czajkowski@physiology.wisc.edu
(608) 265-5863 Phone
(608) 265-5512 Fax

Research Interests
Structure/function relationship in neurotransmitter receptors

The major focus of the lab is on understanding the function and structure of the GABA-A receptor. GABA-A receptors are the major inhibitory neurotransmitter-gated-ion-channels in the brain. While GABA controls the opening of an intrinsic anion-conducting channel, GABA-A receptor function is modulated by a variety of clinically important classes of drugs, including benzodiazepines, barbiturates, volatile anesthetics, neuroactive steroids and alcohol.

Clinically, benzodiazepines, barbiturates and neuroactive steroids are used in the treatments of epilepsy, anxiety and panic disorders as well as other psychiatric illnesses. Recently, mutations in the GABA-A receptor have been linked to human epilepsy. Using computational modeling, protein chemistry, electrophysiological and molecular biological approaches, we are mapping and identifying the amino acid residues that form the binding sites for GABA as well as for therapeutic drugs that bind to the receptor.

Ultimately, a clear understanding of the structural mechanisms coupling GABA binding to anion-channel opening requires, at a minimum, the identification of the amino acid residues which form the binding site pocket for GABA. In addition, we are examining how mutations associated with human epilepsies alter GABA-A receptor function.

We are also interested in examining the assembly and trafficking of the receptor and how interactions with other proteins modulate GABA-A receptor function.

Figure 1 (above left): GABAAR homology model of extracellular NH2 domain. Subunit interfaces involved in forming the GABA and benzodiazepine (BZD) binding sites are labeled. (top view from synaptic side)	Figure 2 (above right): GABA binding site subunit interface. Binding site "Loops" C and F are labeled. Receptor activation may involve movements (red arrows) of these loops.

Past Lab Members:

Selected Publications:
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• Venkatachalan, S. and Czajkowski, C. (2008) A conserved salt-bridge critical for GABAA receptor function and loop C dynamics. Proc. Natl. Acad. Sci. (in press)
   
• Sharkey LM. and Czajkowski C. (2008) Individually monitoring ligand-induced changes in the structure of the GABAA receptor at benzodiazepine binding site and non-binding-site interfaces. Mol Pharmacol. 2008 Jul;74(1):203-12. Epub 2008 Apr 18.
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• Mercado J. and Czajkowski C. (2008) Gamma-aminobutyric acid (GABA) and pentobarbital induce different conformational rearrangements in the GABA A receptor alpha1 and beta2 pre-M1 regions. J Biol Chem. May 30;283(22):15250-7. Epub 2008 Apr 3.
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• Hanson SM, Czajkowski C. (2008) Structural mechanisms underlying benzodiazepine modulation of the GABA(A) receptor. J Neurosci. 2008 Mar 26;28(13):3490-9.
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• Sancar, F., Ericksen, S.S., Kucken, A.M., Teissere, J.A. and Czajkowski, C. (2007) Structural determinants for high affinity zolpidem binding to GABA-A receptors. Mol. Pharmacol 71: 38-46. Epub 2006 Sep 29.
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• Kloda, J. H. and Czajkowski, C. (2007) Agonist-, antagonist-, and benzodiazepine-induced structural changes in the a1Met113-Leu132 region of the GABA-A receptor. Mol. Pharmacol 71: 483-493. Epub 2006 Nov 15.
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• Muroi Y, Czajkowski C, Jackson MB. (2006) Local and Global Ligand-Induced Changes in the Structure of the GABA(A) Receptor Biochemistry Jun 13;45(23):7013-22. PMID: 16752892 [PubMed - in process]
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• Mercado J, Czajkowski C. (2006) Charged residues in the alpha1 and beta2 pre-M1 regions involved in GABAA receptor activation J Neurosci. Feb 15;26(7):2031-40. PMID: 16481436 [PubMed - indexed for MEDLINE]
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• Boileau AJ, Pearce RA, Czajkowski C. (2005) Tandem subunits effectively constrain GABAA receptor stoichiometry and recapitulate receptor kinetics but are insensitive to GABAA receptor-associated protein. J Neurosci. Dec 7;25(49):11219-30. PMID: 16339017 [PubMed - indexed for MEDLINE]
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• Czajkowski C. (2005) Neurobiology: triggers for channel opening Nature. Nov 10;438(7065):167-8. No abstract available. PMID: 16281019 [PubMed - indexed for MEDLINE]
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• Wagner, D.A., Czajkowski, C., and Jones, M.V. (2004) An arginine involved in GABA binding and unbinding but not gating of the GABA-A receptor J. Neurosci. 24: 2733-2741.
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• Sancar, F. and Czajkowski, C. (2004) A GABA-A receptor mutation linked to human epilepsy (g2 R43Q) impairs cell surface expression of abg receptors. J. Biol. Chem. 279: 47034-47039.
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• Newell, J. G., McDevitt, and Czajkowski, C. (2004) Mutation of glutamate 155 of the GABA-A receptor b2 subunit produces a spontaneously open channel: A trigger for channel activation. J. Neurosci. 24: 11226-11235.
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