Laboratory of Ion Channel Biophysics

Barrow Neurological Institute
of St. Joseph's Hospital and Medical Center
Phoenix, Arizona

> Curriculum vitae

Laboratory Focus

Communication between neurons is the basic form of information processing in the brain. This communication is achieved primarily through neurotransmitter-operated ion channels at sites called synapses, where one neuron contacts another. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain. Binding GABA to its postsynaptic receptor type A or C opens a chloride channel and mediates fast synaptic inhibition. 

These GABA-gated ion channels are the major targets for many clinically useful neuroactive compounds such as benzodiazepines, barbiturates, neurosteroids, and general anesthetics. GABA receptor dysfunction is implicated in the origin of a variety neurological and psychiatric disorders, including epilepsy, anxiety, and schizophrenia. Therefore, gaining insight into the mechanisms of GABA-receptor function is fundamental to understanding the pathogenesis of GABA receptor-related disorders and to the development of new drug treatments. The long-term research goal of this laboratory is to elucidate the structural mechanisms of the GABA-receptor function and modulation though an interdisciplinary approach.

Current research projects include the following:

• Structural dynamics underlying GABA-receptor function and modulation using several newly established site-specific fluorescent/luminescent and photochemical techniques, combined with electrophysiological, molecular biological, and computational modeling approaches.
  
• Expression, purification, and functional characterization of the amino-terminal domains of GABA-receptor subunits and nicotinic receptor subunits for structural determination of the agonist-binding domains (in collaboration with Ronald J. Lukas, PhD, Principal Investigator, Neurochemistry Laboratory) and for selection of aptamers (short single-stranded DNA fragments) with high affinity to specific GABA receptor subunits.
  
• Gene expression profiling of GABA-receptor subunits and chloride transporters in hypothalamic hamartoma tissues and single neurons, and their correlation to the receptor function and neuronal excitability (in collaboration with Jie Wu, MD, PhD, Principal Investigator, Neural Physiology Research Laboratory), searching for the mechanism of seizures in hypothalamic hamartoma patients. 

Laboratory Accomplishments

In collaboration with Jie Wu, PhD, from the Division of Neurology, the principal investigator of this laboratory (Yongchang Chang, MD, PhD) has recently received an NIH R21 grant award entitled "GABAergic excitation in human hypothalamic hamartoma" as the co-investigator. 

In the field of GABA receptor research, he has also achieved the following major accomplishments:

• Determined subunit stoichiometry of the major subtype of GABAA receptors.
  
• Developed a single oocyte-binding technique for agonist-binding study and its correlation to channel function. 
  
• Provided the first experimental evidence that binding and gating are tightly coupled in the activation process of a ligand-gated ion channel.
  
• Derived the binding affinities (not directly measurable) of a GABAA receptor at resting and open states.
  
• Discovered that ultraviolet light has differential modulatory effects on the GABAA and GABAC receptors.
  
• Provided the first direct evidence for the cyclic model of the GABAA receptor desensitization kinetics.
  
• Adapted the site-specific fluorescence technique to study structural dynamics of ligand-gated ion channels.
  
• Generated a complete model of the rho-1 GABAC receptor-binding pocket using the substituted cysteine accessibility method.
  
• Identified an evolutionarily conserved allosteric network in the cys-loop family of ligand-gated ion channels using statistical covariance analyses.

Selected References:

Yonghui Chen, Kevin Reilly, Yongchang Chang* (2006).  Evolutionarily conserved allosteric network in the cys-loop family of ligand-gated ion channels revealed by statistical covariance analyses. Journal of Biological Chemistry. 281: 18184-18192.   (*corresponding author)

Sedelnikova, Anna, Craig D. Smith, Stanislav O. Zakharkin, Delores Davis, David S. Weiss, Yongchang Chang* (2005). Mapping rho-1 GABAC receptor agonist binding pocket: constructing a complete model. Journal of Biological Chemistry 280: 1535-1542. (*corresponding author)

Chang, Yongchang and David S. Weiss (2002). Site-specific fluorescence reveals distinct structural changes with GABA receptor activation and antagonism. Nature Neuroscience. 5(11): 1163-1168.

Chang, Yongchang, Emmanuel Ghansah, Yonghui Chen, Jiawei Ye, David S Weiss (2002). Desensitization mechanism of GABAA receptor revealed by repeated single oocyte binding and receptor function. Journal of Neuroscience 22(18):7982-7990.

Liu, Xiaojin, Yongchang Chang, Peter H. Reinhart, Harald Sontheimer (2002). Cloning and characterization of gBK, a novel isoform of BK channels expressed in human glioma cells. Journal of Neuroscience 22(5): 1840-1849.

POSTDOCTORAL FELLOW

Jianliang Zhang, PhD
Postdoctoral Fellow
Laboratory of Ion Channel Biophysics
Division of Neurobiology

Education

2004   PhD, Chinese Academy of Sciences, Beijing, China.
2001   MSc, Fujian Agriculture University, Fuzhou, Fujian province, China.
1998   BSc, Shanxi Agriculture University, Taigu, Shanxi Province, China.

Academic Appointments
4/2006-present     Postdoctoral fellow, Division of Neurobiology, Barrow Neurological Institute, Phoenix, AZ, USA

9/2004-3/2006     Postdoctoral Fellow, Institute of Botany, Chinese Academy of Sciences, Beijing, China

11/2004-3/2005    Visiting Scientist, Commonwealth Scientific and Industrial Research Organization (CSIRO) Entomology, Australia

Publications

Qiao Chuan-Ling, Shen Ben-chang, Xing Jian-Min, Jianliang Zhang, Huang Jing and Zhao De Xiu. High cell density cultivation and characteristics of recombinant protein production of Escherichia coli strain expressing carboxylesterase B1. International Biodeterioration & Biodegradation. (In Press)

Jianliang Zhang, Chuanling Qiao, Wensheng Lan. Purification and some characteristics of recombinant insecticide-resistant mosquito carboxylesterase B1 expressed in Escherichia coli. Enzyme and Microbial Technology, 2005, 36: 648–653.

Jianliang Zhang, Wensheng Lan, Chuanling Qiao, Hong Jiang, Ashok Mulchandani, and Wilfred Chen. Bioremediation of organophosphorus pesticides by surface-expressed carboxylesterase from mosquito on Escherichia coli. Biotechnology Progress, 2004, 20: 1567-1571.

Jian Liang Zhang, Chuan Ling Qiao, Wen Sheng Lan. Detoxification of organophosphorus compounds by recombinant carboxylesterase of insecticide-resistant mosquito and oxime-induced amplification of the enzyme activity. Environmental Toxicology, 2004, 19: 154-159.

Weng-Sheng Lan, Chuan-Ling Qiao, Jian-Liang Zhang, Ben-Chang Sheng. Using insect genes in recombinant microbial systems for bioremediation. Toxicology, 2003, 191: 42.

Ch.-L. Qiao, J. Huang, X. Li, B.-Ch. Shen, J.-L. Zhang. Bioremediation of organophosphate pollutants by a genetically-engineered enzyme. Bulletin of Environmental Contamination and Toxicology, 2003, 70: 455-461.

Yingrong Zhao, Jingsuo Zhang, Chuanling Qiao, Zhiyong Xiao, Jinghong Gao, Jianliang Zhang. Degradation of organophosphorus insecticides on Chinese cabbage using detoxifying enzyme. Journal of Agro-Environmental Science, 2003, 22: 238-239.

Jianliang Zhang, Chuanling Qiao. Novel approaches for remediation of pesticide pollutants. International Journal of Environment and Pollution, 2002; 18: 423-433.

 

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