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Research Interest:
1). Cellular
and Molecular Mechanism of Ca Signaling in Cardiovascular
Function
2). Structure-Function Study of CFTR and
Its Implication to Therapy of Cystic Fibrosis
3). Transgenic Animal Model and Muscle
Physiology
4). Calcium Signaling in Apoptosis and
Cancer Biology
5). Cell-Based High Throughput Screening
Assays
Description:
Our laboratory explores the molecular and cellular
function of membrane proteins, specifically, we are interested
in the structure-function relationship of ion channels,
the molecular basis of genetic diseases caused by mutations
in membrane proteins, and the application of our research
to clinical and pharmaceutical discoveries.
Currently, we
have five projects on going in the laboratory: a) structure-function
study of Ca channels and their role in excitation-contraction
coupling of skeletal and cardiac muscles; b) transgenic
animal models (gene knock out and knock in) to understand
the function of muscle specific proteins in both physiological
and pathophysiological conditions; c) function and regulation
of the CFTR chloride channel and its implication in the
therapeutic intervention of cystic fibrosis; d) Ca signaling
and cytochrome c release in apoptosis; and e) high throughput
screening assays of chemicals targeting at the insect isoform
of ryanodine receptor.
We do our researches
through collaboration with colleagues both on- and off-campuses.
We routinely employ the following experimental tools with
a particular physiological question: a) molecular cloning
and mutagenesis, and heterologous expression of eukaryotic
genes; b) immunological and biochemical assays of recombinant
proteins; c) confocal microscopic imaging of intracellular
ion movement and subcellular localization of GFP-tagged
molecules; d) morphological and biological assays of cells
undergoing apoptosis or treated with different stimuli;
e) NMR structural determination of synthetic peptides or
recombinant proteins; and f) electrophysiological characterization
of single ion channel activities using lipid bilayer reconstitution
and patch clamp measurement.
Our researches
are supported by grants from the National Institutes of
Health (RO1-DK51770, RO1-AG15556, and RO1-CA97357), and
Cystic Fibrosis Foundation, and FMC Corporation.
Publications:
Calcraft PJ, Ruas
M, Pan Z, Cheng X, Arredouani A, Hao X, Tang J, Rietdorf
K, Teboul L, Chuang KT, Lin P, Xiao R, Wang C, Zhu Y, Lin
Y, Wyatt CN, Parrington J, Ma J, Evans
AM, Galione A, Zhu MX. (2009) NAADP mobilizes calcium from
acidic organelles through two-pore channels. Nature. Apr
22. [Epub ahead of print]
Cai C, Weisleder
N, Ko JK, Komazaki S, Sunada Y, Nishi M, Takeshima H,
Ma J. (2009) Membrane repair defects in muscular
dystrophy are linked to altered interaction between MG53,
caveolin-3 and dysferlin. J Biol Chem. Apr 20. [Epub ahead
of print]
Glutamate at position
227 of junctophilin-2 is involved in binding to TRPC3. Woo
JS, Hwang JH, Ko JK, Kim DH, Ma J, Lee
EH. (2009) Mol Cell Biochem. Mar 10. [Epub ahead of print]
Masumiya H, Asaumi
Y, Nishi M, Minamisawa S, Adachi-Akahane S, Yoshida M, Kangawa
K, Ito K, Kagaya Y, Yanagisawa T, Yamazaki T, Ma
J, Takeshima H. (2009) Mitsugumin 53-mediated maintenance
of K+ currents in cardiac myocytes. Channels (Austin). Jan-Feb;3(1):6-11.
Li N, Lin P, Cai
C, Pan Z, Weisleder N, Ma J. (2009) The
amino-terminal peptide of Bax perturbs intracellular Ca2+
homeostasis to enhance apoptosis in prostate cancer cells.
Am J Physiol Cell Physiol. 296(2):C267-72.
Cai, C, Masumiya,
H, Weisleder, N, Matsuda, N, Nishi, Hwang, M, Jae-Kyun,
K, Lin, P, Thornton, A, Zhao, X, Pan, Z, Komazaki, S, Brotto,
M, Takeshima, H and Ma, J (2008) MG53 nucleates
assembly of cell membrane repair machinery. Nat Cell Biol.
11(1):56-64.
Cai C, Masumiya H,
Weisleder N, Pan Z, Nishi M, Komazaki S, Takeshima H, Ma
J. (2008) MG53 regulates membrane budding and exocytosis
in muscle cells. J Biol Chem. 284(5):3314-22.
Liu QH, Zheng YM,
Korde AS, Li XQ, Ma J, Takeshima H, Wang
YX. (2008) Protein kinase C-{epsilon} regulates local calcium
signaling in airway smooth muscle cells. Am J Respir Cell
Mol Biol. 40(6):663-71.
Zhang Q, Hong M,
Duan P, Pan Z, Ma J, You G. (2008) Organic
Anion transporter OAT1 Undergoes constitutive and protein
kinase C-regulated trafficking through a Dynamin- and Clathrin-dependent
pathway. J Biol Chem. 283(47):32570-9.
Li XQ, Zheng YM,
Rathore R, Ma J, Takeshima H, Wang YX.
(2008) Genetic evidence for functional role of ryanodine
receptor 1 in pulmonary artery smooth muscle cells. Pflugers
Arch. Jul 29. [Epub ahead of print]
Zhao X, Weisleder
N, Thornton A, Oppong Y, Campbell R, Ma J, Brotto
M. (2008) Compromised store-operated Ca2+ entry in aged
skeletal muscle. Aging Cell. 7(4):561-8.
Weisleder, N and
Ma, J. (2008) Altered Ca(2+) sparks in
aging skeletal and cardiac muscle Ageing Res. Review
, Mattson, M.P. and Wolkow , C.A. (eds).
Weisleder, N.
and Ma, J. (2008) Immuno-proteomic approach
to excitation contraction coupling in skeletal and cardia
muscle: molecular insights revealed by the mitsugumins.
Cell Calcium 43(1): 1-8
Landstrom AP,
Weisleder N, Batalden KB, Bos JM, Tester DJ, Ommen SR, Wehrens
XH, Claycomb WC, Ko JK, Hwang M, Pan Z, Ma J
, Ackerman MJ. (2007). Mutations in JPH2-encoded junctophilin-2
associated with hypertrophic cardiomyopathy in humans. J.
Mol. Cell Cardiol. 42:1026-35.
Yazawa,
M., Ferrante, C., Feng, J., Mio, K., Ogura, T., Zhang, M.,
Lin, P., Pan, Z., Komazaki, S., Kato, K., Nishi, M., Zhao,
X., Weisleder, N., Sato, C., Ma, J. and
Takeshima, H. (2007) TRIC channels are essential
for handling of intracellular Ca stores. Nature 448:
78-82.
Ko, J. and Ma,
J. (2007) Efficient PCR-based mutagenesis method
applicable to diverse mutagenesis strategies using type
IIs restriction enzymes. Chapter in PCR: Methods Express
S. Hughes and A. Moody, Eds.
Ko, J., Choi,
K., Pan, Z., Lin, P., Weisleder, N., Kim, C.W., Ma,
J. (2007) Tail-anchoring domain of Bfl-1 targets
mitochondria and induces apoptosis by its amphpathic property.
J. Cell Sci. (in press).
Weisleder, N.,
Hirata, Y., Wang, X., Collet, C, Chu , Y, Cheng, H, Takeshima,
H. and Ma, J. (2007) Systemic ablation
of RyR3 alters Ca spark signaling in adult skeletal muscle
. Cell Calcium (in press).
Brotto, M, Weisleder,
N., and Ma, J. (2007) Store-operated Ca
entry in muscle physiology. Curr. Chem. Biol. 1:
87-95.
Hong, M., Tanaka,
K., Pan, P, Ma, J. , and You, G. (2007)
Determination of the external loops and the cellular orientation
of the amino- and the carboxyl termini of the human organic
anion transporter hOAT1. Biochem J. 401: 515-520.
Masumiya, H ,
Cai, C., Nishi, M., Yazawa , M., Ko, J, Weisleder, N., Brotto,
M., Pan, Z., Komazaki, S., Takeshima, H. and Ma,
J. (2007) Functional interaction between MG53 and
caveolin-3 regulates membrane trafficking and remodeling
in skeletal muscle. J. Biol. Chem. (in press).
Phimister AJ,
Lango J, Lee EH, Ernst-Russell M, Takeshima H, Ma
J, Allen PD, Pessah IN. (2007) Conformation-dependent
stability of junctophilin 1 (JP1) and ryanodine receptor
type 1 (RyR1) channel complex is mediated by their hyper-reactive
thiols. J Biol Chem. Jan 19; [Epub ahead of print].
Zhao X, Weisleder
N, Han X, Pan Z, Parness J, Brotto M and Ma J.
(2006) Azumolene inhibits a component of store-operated
calcium entry that is coupled to the skeletal muscle ryanodine
receptor. J. Biol. Chem . 281 :33477-33486.
Weisleder N.,
Brotto M., Komazaki, S., Pan, Z., Nosek, T., Parness, J.,
Takeshima H, and Ma J. (2006) Muscle aging
is associated with ompromised Ca spark signaling and segregated
intracellular Ca release. J. Cell Biol . 174 :
639-645.
Weisleder, N.
and Ma, J. (2006) Ca sparks as a plastic
signal for skeletal muscle health, aging, and dystrophy.
Acta Pharmacol Sin . 27 : 791-798.
Cai, C., Perrante,
C., Lin, P., Foskett, J.K., Boulianne, G., Danielpour, D.,
and Ma, J. (2006) The presenilin-loop peptide
perturbs intracellular Ca homeostasis and accelerates apoptosis.
J. Biol. Chem . 281 :16649-16655.
Yuan X, Xu C,
Pan Z, Keum YS, Kim JH, Shen G, Yu S, Oo KT, Ma
J, Kong AN (2006) Butylated hydroxyanisole regulates
ARE-mediated gene expression via Nrf2 coupled with ERK and
JNK signaling pathway in HepG2 cells. Mol Carcinog .
May 31; [Epub ahead of print].
Hirata Y., Brotto
M., Wang X., Weisleder N., Chu Y., Lin P., Thornton, A.,
Zhao X., Takeshima H., Ma J., Pan Z. (2006)
Uncoupling store-operated Ca entry altered Ca2+ release
from sarcoplasmic reticulum through silencing of junctophilin
genes. Biophys. J 90 : 4418-4427.
Ju J, Hong J,
Zhou JN, Pan Z, Bose M, Liao J, Yang GY, Liu YY, Hou Z,
Lin Y, Ma J, Shih WJ, Carothers AM, Yang
CS. (2005) Inhibition of intestinal tumorigenesis in Apcmin/+
mice by (-)-epigallocatechin-3-gallate, the major catechin
in green tea. Cancer Res . 65 : 10623-31.
Zhao X., Yoshida
M., Brotto L., Takeshima H., Nosek T., Ma J,
Brotto, M. (2005) Enhanced resistance to fatigue and altered
calcium handling properties of sarcalumenin knockout mice.
Physiol. Genomics 23 :72-78.
Paul-Pletzer ,
K , Yamamoto , T. , Ikemoto, N., Jimenez, L.S., Morimoto,
H., Williams, P.G., Ma, J. , and Parness,
J. (2005) Probing a putative dantrolene binding site on
the cardiac ryanodine receptor. Biochem. J. 387 : 905-909.
Ko, J and Ma,
J. (2005) A rapid and efficient PCR-based mutagenesis
method applicable to cell physiology study. Am. J. Physiol.
288 : C1273-C1278.
Wang X., Weisleder
N., Collet C., Zhou J., Chu Y., Brotto M., Hirata Y., Zhao
X., Pan Z., Cheng H., Ma J. (2005) Uncontrolled
calcium sparks act as a dystrophic signal for mammalian
skeletal muscle. Nature Cell Biology 7: 525-530.
Zhou, F., Xu W.,
Hong M., Pan Z., Sinko P.J., Ma J., and
You G. (2005) The role of N-linked glycosylation in protein
folding, membrane targeting and substrate binding of human
organic anion transporter hOAT4. Mol. Pharmacol. 67
: 868-876.
Lin P., Pan Z.,
Zheng, L., Li, N., Danielpour D., Ma J.
(2005) Overexpression of Bax sensitizes prostate cancer
cells to TGF- b induced apoptosis. Cell Research 15
: 150-156.
Brotto M., Nagaraj
R.Y., Nosek L.S., Takeshima H., Nosek T.M., Ma J.
(2004) Defective maintenance of intracellular Ca homeostasis
is linked to increased muscle fatigability in the MG29 null
mice. Cell Research 14 : 373-378.
Zhou F., Pan Z.
Ma J. , You G. (2004) Mutational analysis
of histidine residues I human organic anion transporter
4 (hOAT4). Biochem J. 384: 87-92.
Zhou F., Tanaka
K., Pan Z. Ma J. , You G. (2004) The role
of glycine residues in the function of human organic anion
transporter 4. Mol. Pharmalcol. 65 :1141-1147.
Kamal A., Gross
S., Pan Z., Balklava Z., Ma J., Liu L.
(2004) Nuclear translocation of cytochrome c during apoptosis.
J. Biol. Chem. 279: 24911-24914 (accelerated communication).
Gupta S., Xie
J., Ma J., Davis P.B. (2004) Intermolecular
interacion between R domains of cystic fibrosis transmembrane
conductance regulator. Am. J. Respir. Cell Mol. Biol.
30: 242-248.
Pan Z., Hirata
Y., Nagaraj R.Y., Zhao J., Nishi M., Hayek S.M., Bhat M.B.,
Takeshima H., Ma J. (2004) Co-expression
of MG29 and ryanodine receptor leads to apoptotic cell death:
effect mediated by intracellular Ca2+release. J. Biol.
Chem. 279: 19387-19390 (accelerated communication).
Collet, C.C. and
Ma, J. (2004) Ca-dependent facilitation
and deactivation of store-operated Ca entry in fetal skeletal
muscle. Biophys. J. 87: 268-275.
Lee, J.M., Rho,
S.H., Shin, D.W., Cho, C.H., Park, W.J., Eom, S.H., Ma,
J., Kim, D.H. (2004) Negatively charged amino acids
within the intraluminal loop of ryanodine receptor are involved
in the interaction with triadin. J.Biol. Chem. 279
: 6994-7000.
Ma, J.,
Hayek, S.M., and Bhat, M.B. (2004) Membrane topology and
membrane retention of the ryanodine receptor/Ca release
channel. Cell Biochem. Biophys. 40 (2): 207-224.
Ruehr, M.L., Russell,
M.A., Ferguson , D.G., Bhat, M., Ma, J.,
Damron, D.S., Scott, J.D., Bond, M. (2003) Targeting of
PKA by mAKAP regulates phosphorylation and function of the
skeletal muscle ryanodine receptor. J Biol Chem .
278 : 24831-24836.
Ma, J.,
and Pan, Z. (2003) Retrograde activation of store-operated
Ca channel. Cell Calcium 33: 375-384.
Shin, D.W., Pan,
Z. Lee, M.J., Bhat, M.B., Parness, J., Kim, D.H., and Ma,
J. (2003) A retrograde signal from calsequestrin
for the regulation of store-operated Ca entry in skeletal
muscle. J. Biol. Chem. 278: 3286-3292.
Ma, J.
, and Pan, Z. (2003) Junctional membrane structure and store-operated
Ca entry in muscle cells. Frontiers Biosciences 8:
d242-255.
Paul-Pletzer,
K., Yamamoto, T., Bhat, M.B., Ma, J., Ikemoto,
N., Jimenez, L.S., Morimoto, H., Williams, P.G., and Parness,
J. (2002) Identification of dantrolene-binding site on skeletal
muscle ryanodine receptor. J. Biol. Chem. 277:
34918-34.
Shin, D.W., Pan,
Z., Bandyopadhyay, A. , Bhat, M.B., Kim, D.H., and Ma,
J. (2002) . Ca-dependent interaction between FKBP12
and calcineurin regulates activity of the Ca 2+ release
channel in skeletal muscle. Biophys. J. 83: 2539-2549.
Pan, Z., Nagaraj,
R.Y., Yang, D.M., Nosek, T.A., Takeshima, H., Cheng, H.,
and Ma, J. (2002) Dysfunction of store-operated
Ca channel in muscle cells lacking mg29 gene. Nature
Cell Biol. 4: 379-383.
Bhat, M.B., Ma,
J. (2002). The transmembrane segments of ryanodine
receptor contain an intracellular retention signal for Ca
release channel. J. Biol. Chem. 277: 8597-8601.
Brotto, M.A.B.,
Nagaraj, R.Y., Brotto, L.S., Nosek, C.M., Takeshima, H.,
Ma, J. and Nosek, T. M. (2002) Altered
excitation-contraction coupling machinery and elevated contractile
function in skeletal muscle from mice lacking the MG29 gene.
Am. J. Physiol. (in review).
Xie, J., Adams
, L.M., Zhao, J., Davis , P.B., and Ma, J.
(2002) A short segment of the R domain of CFTR contains
channel stimulatory and inhibitory activities that are separable
by sequence modification. J. Biol. Chem. 277 :
23019-23027.
Staff:
Noah Weisleder,
Ph.D., Postdoctoral Fellow
Ki Ho Park, Ph.D.,
Postdoctoral Fellow
Jae-Kyun Ko, Ph.D.,
Postdotoral Fellow
Xiaoli Zhao, Research
Assistant
Kathy Opitz, Porgram
Assistant
Peihui Lin, Ph.D.,
Research Teaching Specialist I
Chuanxi Cai, Ph.D.,
Research Teaching Specialist IV
Guanping Zhang,
Research Teaching Specialist V
Xiang Wang, Research
Teaching Specialist
Na Li, M.S., Graduate
Student
Christopher Ferrante,
Graduate Student
Angela Thornton,
M.S., Graduate Student
Kyoung-Han Choi,
Graduate Student
Andoria Tjondrokoesoemo,
Graduate Student
Graduate
Program Membership:
Molecular Genetics and Microbiology
Pharmacology
Physiology and
Integrative Biology
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