Michael X. Zhu, Ph.D.
- Postdoctoral Fellow
- Baylor College of Medicine, 1994
- University of Houston, 1991
- University of Houston, 1988
Areas of Interest
Ion channels for calcium signaling
Ion channels for calcium signaling
Calcium ions (Ca2+) play a critical role in cell functions ranging from secretion, contraction, to gene expression and programmed cell death. Intracellular Ca2+ concentrations are tightly controlled in order to generate the diverse patterns of Ca2+ signals with unique spatial and temporal features. The rise in intracellular Ca2+ involves plasma membrane Ca2+ permeable channels and intracellular Ca2+ release channels. Our research focuses on understanding mechanisms regulating stimulus-evoked intracellular Ca2+ increases and their physiological implications. Our previous study on the molecular mechanisms of store- and receptor-operated Ca2+ entry channels had led to gene cloning and functional characterizations of several Transient Receptor Potential Canonical (TRPC) channels. We have performed extensive studies on the regulation of TRPC channel function by Ca2+/calmodulin and other proteins. Our studies also extend to temperature sensitive channels, TRPV1, TRPV3, TRPA1, and TRPM8. These channels are involved in pain sensing, especially inflammatory pain. We focus on understanding the mechanism of regulation of these channels and identification of chemical ligands of therapeutic values for these channels. In a separate study, we investigated molecular mechanism of Ca2+ release from acidic organelles and provided the first evidence that two-pore channels (TPC1, TPC2, and TPC3) are expressed in membranes of endolysosomes and they form Ca2+ release channels that respond to the potent Ca2+ mobilizing messenger, nicotinic acid adenine dinucleotide phosphate (NAADP). The identification of NAADP receptors will pave the way for many future studies on better understanding of Ca2+ signaling mechanisms and the roles of endolysosomes in cell signaling of animal cells.
Currently, we are focusing on the following research areas:
- Molecular mechanism of regulation of TRPC channels. This study is currently aimed to elucidate the mechanisms by which Ca2+-calmodulin and pertussis toxin-sensitive Gi/o proteins activate TRPC4/C5 channels. Ca2+ exerts both positive and negative effects on TRPC4/C5 activation. Some of these are mediated by calmodulin. We have identified multiple calmodulin-binding sites on TRPC4 and C5. We will dissect the specific function of each of these calmodulin-binding sites. We also found that Gi/o proteins are critical for TRPC4/C5 activation. We plan to elucidate the detailed molecular mechanism for this functional coupling using both heterologous and native systems. For the latter, it has been shown that TRPC4 underlies a muscarinic agonist-induced cation current in intestinal smooth muscle cells. We will introduce TRPC4 mutants with specific loss-of-function of certain regulatory features into these cells in TRPC4 knockout mice and study consequences in cholinergic contraction and intestinal motility. Other native functions of TRPC4 and C5 include endothelial migration and neurite outgrowth. We will also examine how Ca2+ and Gi/o regulations affect these functions, combining molecular, pharmacological and physiological techniques.
- High throughput screening of TRPC ligands. Studies of TRP channels have suffered seriously from the lack of specific agonists and antagonists. In collaboration with the Johns Hopkins MLPCN center, we aim to identify lead compounds for TRPC ligands.
- Two-pore channels and NAADP receptors in integrative Ca2+ signaling. This project will expand on our recent finding that TPCs form NAADP receptors. We will examine the roles of the three TPC isoforms in mediating Ca2+ release from different populations of endolysosomes, their pharmacology and physiological functions. The targeting mechanism to endolysosomal populations and trafficking of the TPC-containing vesicles, as well as the involvement of TPCs in endocytosis and exocytosis will also be examined. Moreover, our recent finding suggests that through functional coupling to endoplasmic reticulum Ca2+ release channels, NAADP may serve as a universal trigger for global regenerative Ca2+ waves. This novel hypothesis has significant implications in understanding stimulus-induced intracellular Ca2+ increase under physiological conditions. We aim to examine this hypothesis in both heterologous and native cells.
- Wong CO, Palmieri M, Li J, Akhmedov D, Chao Y, Broadhead GT, Zhu MX, Berdeaux R, Collins CA, Sardiello M, and Venkatachalam K. (2015). Diminished MTORC1-Dependent JNK-Activation Underlies the Neurodevelopmental Defects Associated with Lysosomal Dysfunction. Cell Rep., Sep 29;12(12):2009-20. doi: 10.1016/j.celrep.2015.08.047. Epub Sep 17.
- Zhou Y, Wong CO, Cho KJ, van der Hoeven D, Liang H, Thakur DP, Luo J, Babic M, Zinsmaier KE, Zhu MX, Hu H, Venkatachalam K, and Hancock JF. (2015). Membrane potential modulates plasma membrane phospholipid dynamics and K-Ras signaling. Science., Aug 21;349(6250):873-6. doi: 10.1126/science.aaa5619.
- Feng X, Huang Y, Lu Y, Xiong J, Wong CO, Yang P, Xia J, Chen D, Du G, Venkatachalam K, Xia X, Zhu MX. (2014). Drosophila TRPML forms PI(3,5)P2-activated cation channels in both endolysosomes and plasma membrane. J Biol Chem., 289(7):4262-72.
- Feng X, Xiong J, Lu Y, Xia X, Zhu MX. (2014). Differential mechanisms of action of the mucolipin synthetic agonist, ML-SA1, on insect TRPML and mammalian TRPML1. Cell Calcium, 56, 446-456.
- Fu J, Gao Z, Shen B, Zhu MX. (2014). Canonical transient receptor potential 4 and its small molecule modulators. Sci China Life Sci., 58, 39-47. doi: 10.1007/s11427-014-4772-5. Epub. Dec 5.
- Huang P, Zou Y, Zhong XZ, Cao Q, Zhao K, Zhu MX, Murell-Lagnado R, Dong XP. (2014). P2X4 forms functional ATP-activated cation channels on lysosomal membranes regulated by luminal pH. J Biol Chem., 289, 17658-17667.
- Lin PH, Duann P, Komazaki S, Park KH, Li H, Sun M, Sermersheim M, Gumpper K, Parrington J, Galione A, Evans AM, Zhu MX, Ma J. (2014). Lysosomal two-pore channel subtype 2 (TPC2) regulates skeletal muscle autophagic signaling. J Biol Chem., 290, 3377-3389.
- Ogunbayo OA, Zhu Y, Shen B, Agbani E, Li J, Ma J, Zhu MX, Evans AM. (2014). Organelle-specific subunit interactions of the vertebrate Two Pore Channel family. J Biol Chem., 290, 1086-1095.
- Sun H, Lu L, Zuo Y, Wang Y, Jiao Y, Zeng WZ, Huang C, Zhu MX, Zamponi GW, Zhou T, Xu TL, Cheng J, Li Y. (2014). Kainate receptor activation induces glycine receptor endocytosis through PKC deSUMOylation. Nat Commun., 5, 4980.
- Tian J, Tep C, Benedick A, Saidi N, Ryu JC, Kim ML, Sadasivan S, Oberdick J, Smeyne R, Zhu MX, Yoon SO. (2014). P75 regulates Purkinje cell firing by modulating SK channel activity through Rac1. J Biol Chem., 289, 31458-31472.
- Tian J, Thakur DP, Lu Y, Zhu Y, Freichel M, Flockerzi V, Zhu MX. (2014). Dual depolarization responses generated within the same lateral septal neurons by TRPC4-containing channels. Pflugers Arch., 466, 1301-1316.
- Venkatachalam K, Wong CO, Zhu MX. (2014). The Role of TRPMLs in Endolysosomal Trafficking and Function. Cell Calcium., Oct 28. pii: S0143-4160(14)00163-8. In press.
- Wan X, Lu Y, Chen X, Xiong J, Zhou Y, Li P, Xia B, Li M, Zhu MX, Gao Z. (2014). Bimodal voltage dependence of TRPA1: mutations of a key pore helix residue reveal strong intrinsic voltage-dependent inactivation. Pflugers Arch., 466, 1273-1287.
- Beck A, Speicher T, Stoerger C, Sell T, Dettmer V, Jusoh SA, Abdulmughni A, Cavalié A, Philipp SE, Zhu MX, Helms V, Wissenbach U, Flockerzi V. (2013). Conserved Gating Elements in TRPC4 and TRPC5 Channels. J Biol Chem., 288, 19471-19483.
- Efendiev R, Bavencoffe A, Hu H, Zhu MX, Dessauer CW. (2013). Scaffolding by A-Kinase Anchoring Protein enhances functional coupling between adenylyl cyclase and TRPV1 channel. J Biol Chem., 288, 3929-3937.
- Feng S, Li H, Tai Y, Huang J, Su Y, Abramowitz J, Zhu MX, Birnbaumer L, Wang Y. (2013). Canonical transient receptor potential 3 channels regulate mitochondrial calcium uptake. Proc Natl Acad Sci., USA., 110, 11011-11016.
- Feng X, Huang Y, Lu Y, Xiong J, Wong CO, Yang P, Xia J, Chen D, Du G, Venkatachalam K, Xia X, Zhu MX. (2013). Drosophila TRPML forms PI(3,5)P2-activated cation channels in both endolysosomes and plasma membrane. J Biol Chem. [Epub ahead of print].
- Lin SH, Beane L, Chasse D, Zhu K, Mathey-Prevot B, Chang JT. (2013). Cross-platform prediction of gene expression signatures. PLoS One, 8(11):e79228.
- Tian J, Tep C, Zhu MX, Yoon SO. (2013). Changes in spontaneous firing patterns of cerebellar Purkinje cells in p75 knockout mice. Cerebellum, 12, 300-303.
- Wang X, Li WG, Yu Y, Xiao X, Cheng J, Zeng WZ, Peng Z, Zhu MX, Xu TL. (2013). Serotonin facilitates peripheral pain sensitivity in a manner that depends on the nonproton ligand sensing domain of ASIC3 channel. J Neurosci., 33, 4265-4279.
- Wang YZ, Zeng WZ, Xiao X, Huang Y, Song XL, Yu Z, Tang D, Dong XP, Zhu MX, Xu TL. (2013). Intracellular ASIC1a regulates mitochondrial permeability transition-dependent neuronal death. Cell Death Differ., 20, 1359-1369.
- Xiao X, Zhu MX, Xu TL. (2013). 2-Guanidine-4-methylquinazoline acts as a novel competitive antagonist of A type γ-aminobutyric acid receptors. Neuropharm., 75C, 126-137.
- Zeng WZ, Liu DS, Duan B, Song XL, Wang X, Wei D, Jiang W, Zhu MX, Li Y, Xu TL. (2013). Molecular mechanism of constitutive endocytosis of acid-sensing ion channel 1a and its protective function in acidosis-induced neuronal death. J Neurosci., 33, 7066-78.
- Zhu J, Wu CF, Li X, Wu GS, Xie S, Hu QN, Deng Z, Zhu MX, Luo HR, Hong X. (2013). Synthesis, biological evaluation and molecular modeling of substituted 2-aminobenzimidazoles as novel inhibitors of acetylcholinesterase and butyrylcholinesterase. Bioorg Med Chem., 21, 4218-422.
- Alexander JK, Cox GM, Tian JB, Zha AM, Wei P, Kigerl KA, Reddy MK, Dagia NM, Sielecki T, Zhu MX, Satoskar AR, McTigue DM, Whitacre CC, Popovich PG. (2012). Macrophage migration inhibitory factor (MIF) is essential for inflammatory and neuropathic pain and enhances pain in response to stress. Exp Neurol, 236, 351-362.
- Bavencoffe A, Zhu MX. (2012). TRPC proteins as a link between plasma membrane ion transport and intracellular Ca2+ stores. IN: Groschner, K., Graier, W.F. and Romani C. (eds), Store-Operated Ca2+ Entry (SOCE) Pathways: Emerging Signaling Concepts, Springer Press, Vienna, Austria, Chapter 12, pp.163-175.
- Cheng W, Yang F, Liu S, Colton CK, Wang C, Cui Y, Cao X, Zhu MX, Sun C, Wang KW, Zheng J (2012) Heteromeric heat-sensitive TRP channels exhibit distinct temperature and chemical response. J Biol Chem, 287, 7279-7288.
- Duan B, Liu DS, Huang Y, Zeng WZ, Wang X, Yu H, Zhu MX, Chen ZY, Xu TL. (2012). PI3-kinase/Akt Pathway-Regulated Membrane Insertion of Acid-Sensing Ion Channel 1a Underlies BDNF-Induced Pain Hypersensitivity. J Neurosci, 32, 6351-6363.
- Efendiev R, Bavencoffe A, Hu H, Zhu MX, Dessauer CW. (2012). Scaffolding by A-Kinase Anchoring Protein Enhances Functional Coupling between Adenylyl Cyclase and TRPV1 Channel. J Biol Chem, 2012 Dec 21. [Epub ahead of print].
- Wang X, Zhang X, Dong XP, Samie M, Li X, Cheng X, Goschka A, Shen D, Zhou Y, Harlow J, Zhu MX, Clapham DE, Ren D, Xu H. (2012). TPC proteins are phosphoinositides tide-activated sodium-selective ion channels in endosomes and lysosomes. Cell, 151, 372-383.
- Wang L, Li WG, Huang C, Zhu MX, Xu TL, Wu DZ, Li Y. (2012). Subunit-specific inhibition of glycine receptors by curcumol. J Pharmacol Exp Ther, 343, 371-379.
- Yang Y, Yu Y, Cheng J, Liu Y, Liu DS, Wang J, Zhu MX, Wang R, Xu TL. (2012). A highly conserved salt-bridge stabilizes a rigid signal patch at the extracellular loop critical for surface expression of acid-sensing ion channels. J Biol Chem, 287, 14443-14455.
- Duan B, Wang Y, Chu X-P, Yang T, Yu Y, Huang Y, Cao H, Hansen J, Simon R, Zhu MX, Xiong Z-G, Xu T-L. (2011). Extracellular spermine exacerbates ischemic neuronal injury through sensitization of ASIC1a channels to extracellular acidosis. J Neurosci, 31, 2101-2112.
- Gibon J, Tu P, Bohic S, Richaud P, Arnaud J, Zhu M, Boulay G, Bouron A. (2012). The over-expression of TRPC6 channels in HEK-293 cells favours the intracellular accumulation of zinc. Biochim Biophys Acta, 1808, 2807-2818.
- Hester ME, Murtha MJ, Song S, Rao M, Miranda CJ, Meyer K, Tian J, Boulting G, Schaffer DV, Zhu MX, Pfaff SL, Gage FH, Kaspar BK. (2011). Rapid and Efficient Generation of Functional Motor Neurons From Human Pluripotent Stem Cells Using Gene Delivered Transcription Factor Codes. Mol Ther, 19, 1905-1912.
- Liu B, Yao J, Zhu MX, Qin F. (2011). Hysteresis of gating underlines sensitization of TRPV3 channels. J Gen Physiol, 138, 509-520.
- Luo J, Zhu Y, Zhu MX, Hu H. (2011). Cell-based calcium assay for medium to high throughput screening of TRP channel functions using FlexStation 3. J Vis Exp, (54). doi:pii: 3149. 10.3791/3149.
- Miller M, Shi J, Zhu Y, Kustov M, Tian JB, Stevens A, Wu M, Xu J, Long S, Yang P, Zholos AV, Salovich JM, Weaver CD, Hopkins CR, Lindsley CW, McManus O, Li M, Zhu MX. (2011). Identification of ML204, a Novel Potent Antagonist That Selectively Modulates Native TRPC4/C5 Ion Channels. J Biol Chem, 286, 33436-33446.
- Miller M, Wu M, Xu J, Weaver D, Li M, Zhu MX. (2011). High-throughput screening of TRPC channel ligands using cell-based assays. IN: Zhu MX, editor. TRP Channels. CRC Press, Boca Raton (FL), Chapter 1, pp1-20.
- Ogunbayo OA, Zhu Y, Rossi D, Sorrentino V, Ma J, Zhu MX, Evans AM. (2011). cADPR activates ryanodine receptors while NAADP activates two pore domain channels. J Biol Chem, 286, 9136-9140.
- Sarria I, Ling J, Zhu MX, Gu JG. (2011). TRPM8 acute desensitization is mediated by calmodulin and requires PIP2: distinction from tachyphylaxis. J Neurophysiol, 106, 3056-3066.
- Wang SQ, Zhu MX, Carafoli E. (2011). Ca2+: a versatile master key for intracellular signaling cascades. Sci China Life Sci, 54, 683-685.
- Arredouani A, Evans AM, Ma J, Parrington J, Zhu MX and Galione A .(2010) An emerging role for NAADP-mediated Ca2+ signaling in the pancreatic β-cell. Islets 2, 323-330.
- Colton CK, Kong Q, Lai L, Zhu MX, Seyb KI, Cuny GD, Xian J, Glicksman MA and Lin CL. (2010). Identification of Translational Activators of Glial Glutamate Transporter EAAT2 through Cell-Based High-Throughput Screening: An Approach to Prevent Excitotoxicity. J Biomol Screen 15, 653-662.
- Henderson BJ, Pavlovicz RE, Allen JD, Gonzalez-Cestari TF, Orac CM, Bonnell AB, Zhu MX, Boyd RT, Li C, Bergmeier SC and McKay DB. (2010). Negative Allosteric Modulators that Target Human α4β2 Neuronal Nicotinic Receptors. J Pharmacol Exp Ther 334, 761-774.
- Hu H, Tian J, Zhu Y, Wang C, Xiao R, Herz JM, Wood JD and Zhu MX. (2010). Activation of TRPA1 channels by fenamate non-steroidal anti-inflammatory drugs. Pflugers Arch 459, 579-592.
- Pitt SJ, Funnell T, Sitsapesan M, Venturi E, Rietdorf K, Ruas M, Ganesan A, Gosain R, Churchill GC, Zhu MX, Parrington J, Galione A and Sitsapesan R. (2010) TPC2 is a novel NAADP-sensitive Ca2+-release channel, operating as a dual sensor of luminal pH and Ca2+. J Biol Chem 285, 35039-35046.
- Ruas M, Rietdorf K, Arredouani A, Davis LC, Lloyd-Evans E, Koegel H, Funnell TM, Morgan AJ, Ward JA, Watanabe K, Cheng X, Churchill GC, Zhu MX, Platt FM, Wessel GM, Parrington J and Galione A. (2010). Purified TPC isoforms form NAADP receptors with distinct roles for Ca2+ signaling and endo-lysosomal trafficking. Curr Biol Mar 24 [Epub ahead of print].
- Zhu MX, Evans AM, Ma J, Parrington J and Galione A. (2010). Two-pore channels for integrative calcium signaling. Commun Integr Biol 3, 12-17.
- Zhu MX, Ma J, Parrington J, Calcraft PJ, Galione A and Evans AM. (2010). Calcium signaling via two-pore channels: local or global, that is the question. Am J Physiol Cell Physiol 298, C430-C441.
- Zhu MX, Ma J, Parrington J, Galione A, and Evans AM. (2010). TPCs: endolysosomal channels for calcium mobilization from acidic organelles triggered by NAADP. FEBS Lett 584, 1966-1974.
- Zmuda EJ, Qi L, Zhu MX, Mirmira RG, Montminy MR and Hai T. (2010). The Roles of ATF3, an Adaptive-Response Gene, in High-Fat-Diet-Induced Diabetes and Pancreatic β-Cell Dysfunction. Mol Endocrinol 24, 1423-1433.