Michael X. Zhu, Ph.D.

Areas of Interest

Research Interests

Research Information

Ion channels for calcium signaling

钙离子（Ca2+）在从分泌，收缩到基因表达和程序性细胞死亡的细胞功能中起关键作用。细胞内Ca2+浓度受到严格控制，以生成具有独特的空间和时间特征的Ca2+信号的不同模式。细胞内Ca2+的上升涉及质膜Ca2+可渗透通道和细胞内Ca2+释放通道。我们的研beplay苹果手机能用吗究重点是理解调节刺激诱发的细胞内Ca2+的机制，并增加了它们的生理意义。我们先前关于储存和受体操作的Ca2+进入通道的分子机制的研究导致了几种瞬时受体电位（TRPC）通道的基因克隆和功能特征。我们已经对Ca2+/钙调蛋白和其他蛋白质对TRPC通道功能的调节进行了广泛的研究。我们的研究还扩展到温度敏感的通道TRPV1，TRPV3，TRPA1和TRPM8。这些通道参与疼痛感应，尤其是炎症性疼痛。我们专注于理解这些通道调节的机理以及这些通道治疗值的化学配体的鉴定。在另一项研究中，我们研究了从酸性细胞器中释放Ca2+的分子机制，并提供了第一个证据表明，两孔通道（TPC1，TPC2和TPC3）在内溶液体的膜中表达，它们形成CA2+释放通道，这些通道对有效的响应响应 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:

1. 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.
2. 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.
3. 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.

出版物

出版信息

REFERERNCES

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• Feng X, Xiong J, Lu Y, Xia X,Zhu MX。（2014）。粘膜合成激动剂ML-SA1，昆虫TRPML和哺乳动物TRPML1的作用机理。Cell Calcium, 56, 446-456.
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• 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。（2014）。P75通过通过RAC1调节SK通道活动来调节Purkinje细胞射击。J Biol Chem., 289, 31458-31472.
• Tian J, Thakur DP, Lu Y, Zhu Y, Freichel M, Flockerzi V,Zhu MX。（2014）。通过含TRPC4的通道在相同侧隔神经元内产生的双重去极化反应。pflugers拱门。, 466, 1301-1316.
• Venkatachalam K, Wong CO,Zhu MX。（2014）。TRPML在内溶性贩运和功能中的作用。细胞钙。, 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拱门。, 466, 1273-1287.
• Beck A，Speicher T，Stoerger C，Sell T，Dettmer V，Jusoh SA，Abdulmughni A，CavaliéA，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,朱, 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。(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）。通过A-激酶锚定蛋白脚手架增强了腺苷酸环化酶和TRPV1通道之间的功能耦合。J Biol Chem，2012年12月21日。
• Wang X，Zhang X，Dong XP，Samie M，Li X，Cheng X，Goschka A，Shen D，Zhou Y，Harlow J，Harlow J，Zhu MX，Clapham de，Ren D，Xu H.（2012）。TPC蛋白是phosphoinositidestide-activated sodium-selective ion channels in endosomes and lysosomes.Cell, 151, 372-383.
• Wang L, Li WG, Huang C,Zhu MX李,徐TL,吴DZ, y(2012)。Subunit-specific异烟肼ibition 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,朱m，Boulay G，Bouron A.（2012）。HEK-293细胞中TRPC6通道的过表达有利于锌的细胞内积累。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顾詹。(2011)。TRPM8急性脱敏是我diated 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 MXand Galione A .(2010) An emerging role for NAADP-mediated Ca2+ signaling in the pancreatic β-cell.Islets2, 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 Screen15, 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 Ther334, 761-774.
• Hu H，Tian J，Zhu Y，Wang C，Xiao R，Herz JM，Wood JD和Zhu MX。(2010)。激活TRPA1 fenamate渠道non-steroidal anti-inflammatory drugs.pflugers拱门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 Chem285, 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和Galione A.（2010）。纯化的TPC同工型形成NAADP受体，在Ca2+信号传导和内部溶质体运输中具有不同作用。Curr BiolMar 24 [Epub ahead of print].
• Zhu MX, Evans AM, Ma J, Parrington J and Galione A. (2010). Two-pore channels for integrative calcium signaling.社区Integry Biol3, 12-17.
• Zhu MX，Ma J，Parrington J，Calcraft PJ，Galione A和Evans AM。(2010)。通过两孔通道的钙信号传导：本地或全局，这是问题。AM J Physiol细胞生理298，C430-C441。
• Zhu MX，Ma J，Parrington J，Galione A和Evans Am。(2010)。TPC：由NAADP触发的酸性细胞器的钙动员的内溶性通道。FEBS Lett584, 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 Endocrinol24, 1423-1433.