Education

Postdoctoral Fellow
Baylor College of Medicine, 1994
Ph.D.
University of Houston, 1991
M.S.
University of Houston, 1988

Areas of Interest

Research Interests

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:

  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.

Publications

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REFERERNCES

  • Azoulay IS, Qi X, Rozenfeld M, Liu F, Hu Q, Ben Kasus Nissim, T, Stavsky A, Zhu MX, Xu TL, and Sekler I.  (2022).  ASIC1a enses lactate uptake to regulatemetabolism in neurons. Redox Biol. 51:102253. doi:10.1016/j.redox.2022.102253. PMCID: PMC8894274
  • Feng X, Xiong J, Cai W, Tian JB, and Zhu MX. (2022). The Three Two-Pore Channel Subtypes from Rabbit Exhibit Distinct Sensitivity to Phosphoinositides, Voltage, and Extracytosolic pH. Cells 11(13):2006. https://doi.org/10.3390/cells11132006.
  • Gao Y, Ma R, Weng W, Zhang H, Wang Y, Guo R, Gu X, Yang Y, Yang F, Zhou A, Cheng, J, Chen ZY, Zhu MX, and Li Y. (2022).  TRPV1 SUMOylation suppresses itch by inhibiting TRPV1 interaction with H1 receptors. Cell Rep. 39(11):110972. doi: 10.1016/j.celrep.2022.110972.
  • Kodkandla G, West SJ, Wang, Q, Tewari R, Zhu MX, Akimzhanov AM, Boehning D. (2022). Dynamic S-acylation of the ER-resident protein stromal interaction molecule 1 (STIM1) is required for store-operated Ca2+.  J Biol Chem. 298(9):102303. doi: 10.1016/j.jbc.2022.102303. PMCID: PMC9463532
  • Li, S., Zhao, F., Tang, Q., Xi, C., He, J., Wang, Y., Zhu, M.X., and Cao, Z. (2022). Sarco/endoplasmic reticulum Ca2+ -ATPase (SERCA2b) mediates oxidationinduced endoplasmic reticulum stress to regulate neuropathic pain. Br J
    Pharmacol. 179(9):2016-2036. doi: 10.1111/bph.15744.
  • Liu Z, Xiong J, Gao S, Zhu MX, Sun K, Li M, Zhang G, and Li Y-P. (2022). Ameliorating Cancer Cachexia by Inhibiting Cancer Cell Release of Hsp70 and Hsp90 with Omeprazole. J Cachexia Sarcopenia Muscle 13(1):636-647.
    doi: 10.1002/jcsm.12851. PMCID: PMC8818607
  • Qi X, Lu JF, Huang ZY, Liu YJ, Cai LB, Wen XL, Song XL, Xiong J, Sun PY, Zhang H, Zhang TT, Zhao X, Jiang Q, Li Y, Krishtal O, Hou LC, Zhu MX, and Xu TL. (2022).  Pharmacological validation of ASIC1a as a druggable target for neuroprotection in cerebral ischemia using an intravenously available small molecule inhibitor. Front Pharmacol. 13:849498. doi: 10.3389/fphar.2022.849498. PMCID: PMC8988055.
  • Tian, JB, Yang J, Joslin WC, Flockerzi V, Prescott SA, Birnbaumer L, and Zhu MX.  (2022).TRPC4 and GIRK channels underlie neuronal coding of firing patterns that reflect Gq/11-Gi/o coincidence signals of variable strengths. Proc Natl Acad Sci U S A. 119(20):e2120870119. doi: 10.1073/pnas.2120870119.  PMCID: PMC9171772
  • Tian, Q, Wang P, Xie C, Pang P, Zhang Y, Gao Y, Cao Z, Wu Y, Li W, Zhu MX, Li, D, and Yao J. (2022). Identification of an arthropod molecular target for plant-derived natural repellents. Proc Natl Acad Sci U S A. 119(18):e2118152119. doi: 10.1073/pnas.2118152119. PMCID: PMC9170154
  • Wang Q, Zhu JJ, Wang L, Kan YP, Liu YM, Wu YJ, Gu X, Yi X, Lin ZJ, Wang Q, Lu JF, Jiang Q, Li Y, Liu MG, Xu NJ, Zhu MX, Wang LY, Zhang S, Li WG, Xu TL. (2022). Insular cortical circuits as an executive gateway to decipher threat or extinction memory via distinct subcortical pathways. Nat Commun. 13(1):5540. doi: 10.1038/s41467-022-33241-9. PMCID: PMC9492683.
  • Wang Q, Zhu MX. (2022).  NAADP-Dependent TPC Current. Handb Exp Pharmacol. Jul 29. doi: 10.1007/164_2022_606. Epub ahead of print.
  • Wang Y, Tan L, Jiao K, Xue C, Tang Q, Jiang S, Ren Y, Chen H, El-Aziz TMA, Abdelazeem KNM, Yu Y, Zhao F, Zhu MX, and Cao Z. (2022).  Scutellarein Attenuates Atopic Dermatitis by Selectively Inhibiting Transient Receptor Potential Vanilloid 3. Br J Pharmacol. 179(20):4792-4808, 2022. doi: 10.1111/bph.15913.
  • West SJ, Kodakandla G, Wang Q, Tewari R, Zhu MX, Boehning D, and Akimzhanov AM. (2022).  S-acylation of Orai1 regulates store-operated Ca2+ entry. J Cell Sci. 135(5):jcs258579. doi: 10.1242/jcs.258579. PMCID:
    PMC8255033
  • Zhan Q, Jeon J, Li Y, Huang H, Xiong J, Wang Q, Xu TL, Li Y, Ji FH, Du G, and Zhu MX. (2022). CAMK2/CaMKII activates MLKL in short-term starvation to facilitate autophagic flux. Autophagy 18(4):726-744. doi: 10.1080/15548627.2021.1954348. PMCID: PMC9037428
  • Gao S, Zhao X, Hou L, Ma R, Zhou J, Zhu MX, Pan SJ, and Li Y.  (2021).  The interplay between SUMOylation and phosphorylation of PKCδ facilitates oxidative stress-induced apoptosis. FEBS J. 288(22):6447-6464. doi:10.1111/febs.16050.
  • Jeon J, Bu F, Sun G, Tian JB, Ting SM, Li J, Aronowski J, Birnbaumer L, Freichel M, and Zhu MX. (2021). Contribution of TRPC channels in neuronal excitotoxicity associated with neurodegenerative disease and ischemic stroke. Front Cell Dev Biol. 8:618663. doi: 10.3389/fcell.2020.618663. PMCID:PMC7820370
  • Li WG, Wu YJ, Gu X, Fan HR, Wang Q, Zhu JJ, Yi X, Wang Q, Jiang Q, Li Y, Yuan TF, Xu H, Lu J, Xu NJ, Zhu MX, and Xu TL. (2021). Input associativity underlies fear memory renewal. Natl Sci Rev. 8:nwab004. doi:10.1093/nsr/ nwab004. PMCID: PMC8433092
  • Song XL, Liu DS, Qiang M, Li Q, Liu MG, Li WG, Qi X, Xu NJ, Yang G, Zhu MX, and Xu TL. (2021)  Postsynaptic Targeting and Mobility of Membrane Surface-Localized hASIC1a. Neurosci Bull. 37(2):145-165. doi:10.1007/s12264-020-00581-9. PMCID: PMC7870742
  • Wang H, Yang P, Lu Y, Wang J, Jeon J, Wang Q, Tian JB, Zang B, Yu Y, and Zhu MX. (2021). Mechanism of proton inhibition and sensitization of cation channel TRPV3. J Gen Physiol. 153(2):e202012663. doi:10.1085/jgp.202012663. PMCID: PMC7745752
  • Wang Y, Li H, Xue C, Chen H, Xue Y, Zhao F, Zhu MX, and Cao Z. (2021).  TRPV3 enhances skin keratinocyte proliferation through EGFR-dependent signaling pathways. Cell Biol Toxicol. 37(2):313-330. doi:10.1007/s10565-020-09536-2. PMID: 32535744
  • Wong CO, Karagas NE, Jung J, Wang Q, Rousseau MA, Chao Y, Insolera R, Soppina P, Collins CA, Zhou Y, Hancock JF, Zhu MX, and Venkatachalam K. (2021). Regulation of longevity by depolarization-induced activation of PLC-β-IP3R signaling in neurons. Proc Natl Acad Sci U S A. 118(16):e2004253118. doi: 10.1073/pnas.2004253118. PMCID:PMC8072327
  • Liu H, Weng W, Guo R, Zhou J, Xue J, Zhong S, Cheng J, Zhu MX, Pan SJ, and Li Y. (2020). Olig2 SUMOylation protects against genotoxic damage response by antagonizing p53 gene targeting. Cell Death Differ. 27(11):3146-3161. doi:10.1038/s41418-020-0569-1. PMCID: PMC7560653
  • Lopez ER, Carbajal AG, Tian JB, Bavencoffe A, Zhu MX, Dessauer CW, and Walters ET. (2020). Serotonin enhances depolarizing spontaneous fluctuations, excitability, and ongoing activity in isolated rat DRG neurons via 5-HT4 receptors
    and cAMP-dependent mechanisms. Neuropharmacology. 184:108408. doi: 10.1016/j.neuropharm.2020.108408. PMCID: PMC7856035
  • Ma R, Ma L, Weng W, Wang Y, Liu H, Guo R, Gao Y, Tu J, Xu T-L, Cheng J, Zhu MX, Zhou A, and Li Y. (2020). DUSP6 SUMOylation protects cells from oxidative damage via direct regulation of Drp1 dephosphorylation. Sci Adv. 6(13):eaaz0361. doi: 10.1126/sciadv.aaz0361. PMCID: PMC7096176
  • Mohandass A, KrishnanV, Gribkova ED, Asuthkar S, Baskaran P, Nersesyan Y, Hussain Z, Wise LM, George RE, Stokes N, Alexander BM, Cohen AM, Pavlov EV, Llano DA, Zhu MX, Thyagarajan B, and Zakharian E. (2020). TRPM8 as the rapid testosterone signaling receptor: Implications in the regulation of dimorphic sexual and social behaviors. FASEB J. 34(8):10887-10906. doi: 10.1096/fj.202000794R. PMCID: PMC7496617
  • Savic Azoulay I, Liu F, Qin H, Rozenfeld M, Ben Kasus Nissim T, Zhu MX, Sekler I, and Xu TL. (2020). ASIC1a Channels Regulate Mitochondrial Ion Signaling and Energy Homeostasis in Neurons. J Neurochem. 153(2):203-215. doi:10.1111/jnc.14971. PMCID: PMC7180113
  • Shen X, Wang Q, Lin Y, Sreekrishna K, Jian Z, Zhu MX, and Tian J. (2020).  Voltage-dependent modulation of TRPA1 currents by diphenhydramine. Cell Calcium 90:102245, 2020. doi: 10.1016/j.ceca.2020.102245. PMCID:PMC7959105
  • Wang JJ, Liu F, Yang F, Wang YZ, Qi X, Li Y, Hu Q, Zhu MX, Xu TL. (2020).  Disruption of auto-inhibition underlies conformational signaling of ASIC1a to induce neuronal necroptosis. Nat Commun. 11(1):475. doi:10.1038/s41467-019-13873-0. PMCID: PMC6981194
  • Zhao X, Xia B, Cheng J, Zhu MX, and Li Y. (2020).  PKCε SUMOylation is required for mediating the nociceptive signaling of inflammatory pain. Cell Rep. 33(1):108191. doi:10.1016/j.celrep.2020.108191