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Zheng Fan, Ph.D. Professor
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Voice: (901)
448-2872
Email: zfan@physio1.utmem.edu |
Full CV
Education
Ph.D., Tokyo Medical
and Dental University, Japan, 1992
Postdoctoral Training, University of
Chicago, Illinois, 1992-3
Research
Interest
My research interest is to understand the function and
structure of ion channels.
One area of my research is studying inwardly rectifying
potassium channels, specifically their structure-function relationships, gating
mechanisms, and regulation under physiological conditions. This is a long-term
research direction of this laboratory. Our present interest is on ATP-sensitive
potassium (KATP) channels, a subfamily of inwardly rectifying potassium
channels. ATP plays a pivotal role in the energy economy of the cell.
Additionally, in many cell types such as muscle cells and pancreatic islet
beta-cells, ATP has important roles in transducing cellular signals that
involve a particular type of potassium channel: the KATP channel. In islet
beta-cells, for example, insulin release in response to hyperglycemia is
mediated by a remarkable inhibition of the KATP channel. My laboratory has been
working on research concerned with the molecular basis for the biophysical
activity of KATP channels. Among the goals of this research is to increase our
understanding of how KATP channels couple energy metabolism to cellular
processes under physiological and pathophysiological circumstances. Another
goal of this research is to elucidate the roles of membrane phospholipids in
regulating KATP channels and other inwardly rectifying potassium channels. This
part of the research project builds on our previous pioneering studies in this
area. Currently, we are interested in the cellular and molecular processes
associated with this regulatory mechanism and their physiological relevance.
The second area of my research deals with the gating
process of a bacterial potassium channel, KcsA. KcsA is the first ion channel
of known structure, and its X-ray structures are available for several conformations.
A great amount of evidence has indicated that the pore region of this channel,
which contains a selectivity filter for potassium ions, has a structure similar
to that of most mammalian potassium channels. KcsA is therefore used as a
prototypic model to study the structural basis of ion channel function. In 2005
we reported for the first time an inactivation process occurring at the
selectivity filter of the KcsA channel. Ion channel inactivation describes a
channel closing process that follows channel activation. Activation-coupled
inactivation allows ion channels to block ion flow in the presence of a
stimulating signal, whereby ion channels control fundamental physiological
processes such as formation of activation potentials in excitable cells. Two
major mechanisms of such inactivation have been identified. Among them, N-type
inactivation has been analyzed in unprecedented, definitive structural detail.
Prior to our study, the understanding of another type of inactivation, known as
C-type inactivation, was based on functional studies. These studies implicated
that C-type inactivation was related to the selectivity filter. However,
although structural data obtained from KcsA showed an inactivated conformation
at the selectivity filter, activation-coupled inactivation had not been
observed in this channel. This is
inconsistent with the selectivity filter hypothesis, thereby puzzling
researchers. Our 2005 paper demonstrates that the KcsA channel has an activation
process and an associated inactivation process. Furthermore, the inactivation
of KcsA exhibits many similarities to C-type inactivation of mammalian
channels. These findings provide a rationale that links the structural data
available for KcsA to the C-type inactivation, and have justified KcsA to be a
simplified but compelling model for deciphering the structural basis of channel
inactivation.
Most recently, our work has also focused on the
pathogenesis of maternally inherited dilated cardiomyopathy (DCM) and
arrhythmias associated with sodium channel mutations. This is a new area of
research that was brought to this laboratory through an extramural
collaborative research activity. Our colleagues at the Shanghai Institute of
Cardiovascular Diseases have identified the disease in a patient family, and
the genetic study has localized a mutant gene locus that encodes the cardiac
sodium channel SCN5A. We performed functional studies on the corresponding
mutant sodium channel and determined the phenotypic changes caused by this
mutation. A major finding of our study is that both DMC and arrhythmias in the
patients of the family are causally associated with the sodium channel
mutation. Previously, it was believed that cardiac sodium channel mutations
primarily caused abnormalities of electrical activity in heart, such as Long-QT
Syndrome, Brugada Syndrome, and conductance block. Our study suggests a
possible pathogenic link between progressive DCM and sodium channel mutations.
Two recent papers also reported an association between SCN5A mutations and
cardiomyopathy. Our study has
expanded the repertoire of SCN5A mutations associated with DCM. We are
currently studying why and how some SCN5A mutations cause structural damage to
the heart muscle.
Current
Techniques Utilized
1. Methods of Electrophysiology: Patch-clamp recordings
(whole-cell/single-channel configurations), single-channel recording in planar
lipid bilayer, fluorescent measurement of cross-membrane ion flex
2. Methods of Molecular Biology: Site-directed mutagenesis,
cloning of cDNA, analysis of mRNA expression using Northern
blotting/quantitative RT-PCR/RNAase protection
3. Methods of Protein Biochemistry: Chromatography purification
of membrane proteins, detection of proteins using
immunoblotting/immunoprecipitation, reconstitution of membrane proteins into
planar lipid bilayer/protoliposomes.
4. Methods of Lipid Biochemistry: Thin layer chromatography
5. Methods of Cell Biology: Cell culture, transfection/infection
of mammalian cells, immunostaining and confocal visualization of protein
distribution in cultured cells
Selected
Recent Publications
1.
Ge J., Sun A., Paajanen V., Wang S., Su
C., Yang Z., Li Y., Wang S., Jia J., Wang K, Zou Y, Gao L., Wang K., Fan Z. (2008) Molecular and clinical characterization of a novel
SCN5A mutation associated with atrioventricular block and dilated
cardiomyopathy. Circulation: Arrhythmia and Electrophysiology
1:83-92. (Note: This paper was published with an accompanying editorial article; both
were selected as the only two “Editor’s Picks” in the same issue of the
journal)
2.
Vaithianathan T., Liu P., Asuncion-Chin
M., Fan
Z., Dopico A.M. (2008) Direct regulation of BK channels by
phosphatidylinositol 4, 5-bisphosphate as a novel signaling mechanism. J. Gen.
Physiol. 132:13-28. (Note: This paper was published with an accompanying
commentary article)
3.
Nishimura H., Yang Y., Lau K., Kuykindoll
R., Fan
Z., Yamaguchi K., and Yamamoto T. (2007) Aquaporin-2 water
channel in developing quail kidney:
Possible role in programming adult fluid homeostasis. Am. J. Physiol.
(Regul Integr Comp Physiol) doi:10.1152/ajpregu.00163
4.
Yang Y., Cui Y., Fan Z., Cook G., and Nishimura H. (2006) Two distinct aquaporint-4 cDNAs
isolated from medullary cone of quail kidney. Comp. Biochem. Physiol. 147:84-93
5.
Gao L., Mi X., Paajanen V., Wang K., and Fan Z. (2005) From the Cover: Activation-coupled inactivation in the bacterial
potassium channel KcsA. Proc Natl Acad Sci U S A. (via track II) 102:17630-17635. (Note:
This paper was featured with four others on the
cover of Dec 6, 2005 issue of the journal)
6.
Gosmanov A.R., Fan Z., Mi X., Schneider E.G., and Thomason D.B. (2004) ATP-sensitive
potassium channels mediate hyperosmotic stimulation of NKCC in slow-twitch
muscle. Am. J. Physiol (Cell Physiol) 286:C586-595
7.
Yang Y., Cui Y., Wang W., Zhang L.,
Bufford L., Sasaki S., Fan Z., Nishimura H. (2004) Molecular and
functional characterization of a vasotocin-sensitive aquaporin water channel in
quail kidney. Am. J. Physiol. (Regul Integr Comp Physiol) 287:R915-924
8.
Fan Z., Gao L., and Wang W. (2003)
Phosphatidic acid stimulates cardiac KATP channels like phosphatidylinositols,
but with novel gating kinetics. Am. J. Physiol (Cell Physiol). 284: C94-C102
9.
Wang C., Wang K., Wang W., Cui Y., and Fan Z. (2002) Compromised ATP binding as a mechanism of
phosphoinositide modulation of ATP-sensitive K+ channels. FEBS Lett.
532:177-182
10.
Cui Y., and Fan Z. Mechanism of Kir6.2 channel inhibition by sulfhydryl modification:
pore block or allosteric gating?
(2002) J. Physiol. 540: 731-741
11.
Cui Y., Wang W., and Fan Z. (2002) Cytoplasmic vestibule of the weak inward rectifier Kir6.2
potassium channel. J. Bio. Chem. 277: 10523-10530
Revised 10/08
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