Jianjie Ma University Professor UMDNJ Department of Physiology & Biophysics RWJMS Research Building. Room 162 675 Hoes Lane Piscataway. NJ 08854-5635 (732) 235-4494 FAX - 4483 maj2@umdnj.edu

Structure-function studies of ion channels. transgenic animal models of cardiovascular research. signal transduction in cancer biology curing cancer. sexually transmitted disease

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.

Selected Publications

Weisleder N, Ferrante C, Hirata Y, Collet C, Chu Y, Cheng H, Takeshima H, Ma J. (2007) Systemic ablation of RyR3 alters Ca(2+) spark signaling in adult skeletal muscle.
Cell Calcium. Apr 3; [Epub ahead of print]

Phimister AJ, Lango J, Lee EH, Ernst-Russell MA, 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. 282(12):8667-77.

Hong M, Tanaka K, Pan Z, Ma J, You G. (2007) Determination of the external loops and the cellular orientation of the N- and the C-termini of the human organic anion transporter hOAT1. Biochem J. 401(2):515-20.

Zhao X, Weisleder N, Han X, Pan Z, Parness J, Brotto M, Ma J. (2006) Azumolene inhibits a component of store-operated calcium entry coupled to the skeletal muscle ryanodine receptor. J Biol Chem. 281(44):33477-86.

Weisleder N, Brotto M, Komazaki S, Pan Z, Zhao X, Nosek T, Parness J, Takeshima H, Ma J. (2006) Muscle aging is associated with compromised Ca2+ spark signaling and segregated intracellular Ca2+ release. J Cell Biol. 174(5):639-45.

Xu C, Yuan X, Pan Z, Shen G, Kim JH, Yu S, Khor TO, Li W, Ma J, Kong AN. (2006) Mechanism of action of isothiocyanates: the induction of ARE-regulated genes is associated with activation of ERK and JNK and the phosphorylation and nuclear translocation of Nrf2.
Mol Cancer Ther. 5(8):1918-26.

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. 45(11):841-50.

Cai C. Lin P. Cheung KH. Li N. Levchook C. Pan Z. Ferrante C. Boulianne GL. Foskett JK. Danielpour D. Ma J. (2006) The presenilin-2 loop Peptide perturbs intracellular Ca2+ homeostasis and accelerates apoptosis. J Biol Chem. 281(24):16649-55.

Hirata Y. Brotto M. Weisleder N. Chu Y. Lin P. Zhao X. Thornton A. Komazaki S. Takeshima H. Ma J. Pan Z. (2006) Uncoupling store-operated Ca2+ entry and altered Ca2+ release from sarcoplasmic reticulum through silencing of junctophilin genes. Biophys J. 90(12):4418-27.

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(22):10623-31.

Zhao X. Yoshida M. Brotto L. Takeshima H. Weisleder N. Hirata Y. Nosek TM. Ma J. Brotto M. (2005) Enhanced resistance to fatigue and altered calcium handling properties of sarcalumenin knockout mice. Physiol Genomics. 23(1):72-8.

Wang X. Weisleder N. Collet C. Zhou J. Chu Y. Hirata Y. Zhao X. Pan Z. Brotto M. Cheng H. Ma J. (2005) Uncontrolled calcium sparks act as a dystrophic signal for mammalian skeletal muscle. Nat Cell Biol. 7(5):525-30.

Ko JK. Ma J. (2005) A rapid and efficient PCR-based mutagenesis method applicable to cell physiology study. Am J Physiol Cell Physiol. 288(6):C1273-8.

Paul-Pletzer K. Yamamoto T. Ikemoto N. Jimenez LS. Morimoto H. Williams PG. Ma J. Parness J. (2005) Probing a putative dantrolene-binding site on the cardiac ryanodine receptor. Biochem J. 387(Pt 3):905-9.

Zhou F. Xu W. Hong M. Pan Z. Sinko PJ. Ma J. 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(3):868-76.

Zhou F. Pan Z. Ma J. You G.(2004) Mutational analysis of histidine residues in human organic anion transporter 4 (hOAT4). Biochem J. 384(Pt 1):87-92.

Collet C. Ma J. (2004) Calcium-dependent facilitation and graded deactivation of store-operated calcium entry in fetal skeletal muscle. Biophys J. 87(1):268-75.

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 Pharmacol. 65(5):1141-7.

Nur-E-Kamal A. Gross SR. Pan Z. Balklava Z. Ma J. Liu LF. (2004) Nuclear translocation of cytochrome C during translocation.J. Biol Chem. (in press)

Pan Z. Hirata Y. Nagaraj RY. Zhao J. Nishi M. Hayek SM. Bhat MB. Takeshima H. Ma J. (2004) Coexpression of mg29 and ryanodine receptor leads to apoptotic cell death-effect mediated by intracellular Ca2+ release. J. Biol Chem. 279: 19387-19390.

Ruehr. M.L.. Russell. M.A.. Ferguson. D.G.. Bhat. M.. Ma. J.. Damron. D.S.. Scott. J.D.. Bond. M. (2004) Targeting of PKA by mAKAP regulates phosphorylation and function of the skeletal muscle ryanodine receptor. J. Biol Chem. 278: 24831-24836.

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: 207-224.

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.

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.

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 Ca2+ release channel in skeletal muscle. Biophys. J. 83: 2539-2549.

Ma. J. and Pan. Z. (2003) Junctional membrane structure and store-operated Ca entry in muscle cells. Frontiers Biosciences 8: d242-255.

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.

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.

Yang. D.M.. Pan. Z.. Takeshima. H.. Cheng. H.. and Ma. J. (2001) RyR3 amplifies RyR1-mediated Ca-induced Ca release in neonatal mammalian skeletal muscle. J. Biol. Chem. (in press).

Chipuk. J.. Bhat. M.B.. Ma. J.. and Danielpour. D. (2001) Bcl-xL blocks TGF-b mediated apoptosis by inhibiting cytochrome c release not by directly antagonizing Apaf-1-dependent caspase activation in prostate epithelial cells. J. Biol. Chem. 276: 26614-26621.

Pan. Z.. Bhat. M.B.. Nieminen. A.L.. and Ma. J. (2001) Synergistic movements of Ca and Bax in cells undergoing apoptosis. J. Biol. Chem. 276: 32257-32263.

Xie. J.. Zhao. J.. Davis. P.B.. and Ma. J. (2000) Conformation. independent of charge. in the R domain affects CFTR channel openings. Biophys. J. 78: 1293-1305.

Ma. J. (2000) Stimulatory and inhibitory functions of the R domain on CFTR chloride channel. News Physiol. Sci. 15: 154-158.

Xu. X.. Bhat. M.B.. Nishi. M.. Takeshima. H.. and Ma. J. (2000) Molecular cloning of cDNA encoding a Drosophila ryanodine receptor and functional studies of the carboxyl-terminal calcium release channel. Biophys. J. 78: 1270-1281.

Hayek. S.M.. Zhu. X.. Bhat. M.B.. Takeshima. H.. Valdivia. H.. and Ma. J. (2000) Functional characterization of a Ca regulatory domain in the skeletal muscle ryanodine receptor. Biochem. J. 351: 57-65.

Pan. Z.. Damron. D.. Nieminen. A.L.. Bhat. M.B.. and Ma. J. (2000) Depletion of intracellular Ca by caffeine and ryanodine induces apoptosis of Chinese hamster ovary cells transfected with ryanodine receptor. J. Biol. Chem. 275: 19978-19984.

Nagaraj. R.Y.. Nosek. C.. Brotto. M.A.. Nishi. M.. Takeshima. H.. Nosek. T.M.. and Ma. J. (2000). Increased susceptibility to fatigue of slow and fast twitch muscles from mice lacking the MG29 gene. Physiol. Genomics 4: 43-49.

Shin. D.W.. Ma. J.. and Kim. D.H. (2000) The asp-rich region of calsequestrin interacts with triadin and binds to calcium. FEBS Lett. 486: 178-182.