Mechanism of hydrogen sulphide mediated signaling cascade through n methyl d aspartate receptors

Mechanism of Hydrogen Sulphide-mediated Signaling Cascade through N-methyl-D-aspartate Receptors CHEN MINGHUI JESSICA (BSc (2nd Upp Hons), NUS) A THESIS SUBMITTED FOR THE DEGREE OF MASTER OF SCIENCE DEPARTMENT OF BIOCHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE 2008 Acknowledgements I am more appreciative than I can express to my supervisors, Dr Steve Cheung Nam Sang of Department of Biochemistry, NUS, Prof Philip Moore of Department of Pharmacology, NUS and, Dr Deng Lih Wen of Department of Biochemistry, NUS for their invaluable advices, motivations and endless encouragement that have been given to me I am grateful to their patient guidance supervision towards the completion of this project and sacrificing their precious time to meet me on a regular basis despite his busy schedule I would also like to show my gratefulness to the help and guidance Mr Jayapal Manikandan of Department of Physiology and Prof Maxey Chung, and Miss Tan Gek San of Department of Biochemistry had rendered in my course of research, that had truly benefited me in many ways Here I would like to highlight and thank Dr Peng Zhao Feng and Miss Chong Chai Chien for their help in troubleshooting in the course of my experiments and sharing of their laboratory knowledge with me Thanks also to my peers, Miss Chang Jaw Shin and Miss Seet Sze Jee for their great friendship and wonderful encouragements given to me in the course of this project Last but not least, a very big thank you to all those whom I have unintentionally left out in this list and have in one way or another help in my Masters project Content Page List of Figures i List of Tables ii List of Abbreviations iii List of Publications iv Summary vi Chapter 1: Introduction 1.1 Hydrogen Sulphide (H2S) 1.1.1 Toxicological properties 1.1.2 Chemical properties 1.1.3 Biological properties 1.1.3.1 In vivo synthesis of H2S 1.1.3.2 Occurrence of H2S in mammalian body 1.1.3.3 Degradation of H2S Physiological and patho-physiological functions 1.1.4.1 Central Nervous System (CNS) 1.1.4.2 Cardiovascular System 1.1.4.3 Endocrine System 1.1.4.4 Immune System 1.1.4 1.2 Glutamate Receptors (GluRs) 1.2.1 10 Ionotropic GluRs 11 1.2.1.1 N-methy-D-Asparatate (NMDA) receptors 11 1.2.1.2 Alpha-amino-3-hydroxy-5-methyl-4- 11 isoxazolepropionic Acid (AMPA) receptors 1.2.2 1.3 1.2.1.3 Kainate (KA) receptors 12 Metabotropic GluRs (mGluRs) 12 NMDA receptors: A major subfamily of GluR superfamily 12 1.3.1 Physiological roles of NMDA receptors 13 1.3.2 Patho-physiological role of NMDA receptors: 14 Excitotoxicity in neurons 1.4 Association between H2S and NMDA receptors in CNS 16 1.5 Association between H2S and NMDA receptors in 16 neurodegeneration 1.6 Proposed hypothesis 19 1.7 Aims and Objectives 20 Chapter 2: Methodology 21 2.1 Mouse Neocortical Neuronal Cell Culture Preparation 22 2.2 NaHS Stock Preparation 23 2.3 Cell Lysate Preparation using RIPA Buffer 23 2.4 Western Blotting of RIPA-extracted samples 24 2.5 MTT Reduction Assay 26 2.6 LDH release assay 27 2.7 Lysosomal membrane stability assay 27 2.8 Total RNA Extraction and Isolation 28 2.9 Determination of RNA Concentration 28 2.10 Checking of RNA Quality 29 2.11 cDNA Synthesis/ Reverse transcription 30 2.12 Real-time Polymerase Chain Reaction (Real-time PCR) 31 2.13 Microarray analysis 32 2.13.1 Microarray experiment using Illumina Mouse Ref8 Ver.1.1 32 hybridization beadchips 2.13.2 Microarray data collection and analysis 2.14 Proteomics analysis using 2-DIGE 34 34 2.14.1 Whole cell lysate harvesting 34 2.14.2 Protein clean-up and quantification 35 2.14.3 Sample Labeling with CyDye DIGE Fluors (minimal dye) 36 2.14.4 Rehydration of immobilized pH gradient (IPG) gel strips 37 2.14.5 First Dimension – Isoelectric Focusing (IEF) 38 2.14.6 Second Dimension – SDS-PAGE 39 2.14.7 Image acquisition 40 2.14.8 Image analysis 41 2.14.9 Silver staining 41 2.14.10In gel proteolytic digestion 42 2.14.11Matrix-assisted Laser Desorption/Ionization Time of 45 Flight/Time of Flight Mass Spectrometry - Mass Spectrometry (MALDI-TOF/MS-MS) 2.15 Statistical analysis 46 Chapter 3: Results 3.1 H2S effects on mouse primary cortical neurons 3.1.1 Concentration-dependent decrease in cell viability of 47 48 NaHS-treated neurons 3.1.2 Induction of apoptosis by NaHS on day mouse primary 50 cortical neurons 3.2 Involvement of GluRs in H2S-mediated neuronal apoptosis 3.2.1 Potentiation of L-glutamate-induced toxicity upon H2S 52 53 application 3.2.2 Differential expression of GluRs in mouse primary 55 cortical neurons in vitro 3.2.3 NMDA and KA receptors implicated in H2S-mediated 56 neuronal death 3.2.4 Dose-dependent decrease in cell viability in NMDA- 58 treated neurons 3.2.5 Calpain activation observed in H2S- and NMDA-mediated 59 neuronal death 3.3 Global gene profiles of H2S- and NMDA-mediated neuronal 61 deaths 3.3.1 Differential gene expression of genes encoding proteins 64 involved in apoptosis 3.3.2 Differential gene expression of genes encoding proteins involved in endoplasmic reticulum (ER) stress 66 3.3.3 Differential gene expression of genes encoding proteins 68 involved in calcium homeostasis and binding 3.3.4 Differential gene expression of genes encoding proteins 70 involved in cell survival 3.3.5 Differential gene expression of genes encoding proteins 71 involved in mitotic cell cycle regulation 3.3.6 Differential gene expression of genes encoding heat shock 73 proteins (Hsps) and chaperones 3.3.7 Differential gene expression of genes encoding proteins 75 involved in ubiquitin-proteasome system (UPS) 3.3.7.1 Comparison of global gene profiles between H2S-, 78 NO- and lactacystin-mediated neuronal deaths 3.3.8 Differential gene expression of genes encoding water and 81 ion channels associated with apoptotic volume decrease (AVD) 3.4 Validation of Microarray data 85 3.4.1 Validation of microarray analysis via real-time PCR 86 3.4.2 Validation of microarray analysis via Western blotting 87 3.4.3 Validation of microarray analysis via proteomics approach 89 3.4.4 Validation of microarray analysis via lysosomal 93 membrane stability assessment 95 Chapter 4: Discussion 4.1 Elucidation of essentiality of various cell death-related pathways 96 in H2S-mediated apoptosis through microarray analysis 4.1.1 Role of the apoptotic mechanism in cell death and its 97 relevance in H2S-mediated neuronal death 4.1.2 Role of the ER stress in cell death and its relevance in 100 H2S-mediated neuronal death 4.1.3 4.1.2.1 CCAAT/enhancer binding protein (C/EBP) 102 4.1.2.2 DNA damage-inducible transcript (Ddit3) 103 Role of the calcium homeostasis and binding in cell death 104 and its relevance in H2S-mediated neuronal death 4.1.4 Role of the pro-survival pathway in cell death and its 106 relevance in H2S-mediated neuronal death 4.1.5 Role of the mitotic cell cycle regulation in cell death and 107 its relevance in H2S-mediated neuronal death 4.1.5.1 Growth arrest and DNA-damage-inducible 45 109 gamma (Gadd45) 4.1.5.2 4.1.6 Ubiquitin-conjugating enzyme E2N (Ube2n) Role of Hsps and chaperones in cell death and its 110 111 relevance in H2S-mediated neuronal death 4.1.6.1 Sulfiredoxin (Srxn1 / Npn3) 112 4.1.6.2 Metallothioneins 113 4.1.6.3 Heme oxygenase (Hmox1) 114 4.1.7 4.1.6.4 Heat shock protein 27 (Hsp27 / Hspb8) 115 4.1.6.5 Heat shock protein 47 (Hsp47 / Serpinh1) 117 Role of the UPS in cell death and its relevance in H2S- 118 mediated neuronal death 4.1.8 4.1.7.1 Ubiquitin C-terminal hydrolase L1 (UchL1) 119 4.1.7.2 Proteasome subunit beta (Psmb2) 120 Role of the AVD in cell death and its relevance in H2S- 121 mediated neuronal death 4.2 Proposed signaling cascade of H2S-mediated signaling cascade 122 through NMDA receptor 4.3 Similarities and differences between H2S- and NMDA-mediated 126 neuronal deaths 4.4 Comparison of UPS gene profiles among H2S, NO and lactacystin 128 neuronal treatments 4.5 Conclusion Chapter 5: References 130 132 List of Figures Page Figure 3.1.1 Concentration-dependent 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Genes Dev 12, 982-995 152 [...]... transcriptional increase in cathepsins, an indication of calpains-cathepsin phenomenon Since low H2S levels, and high protein nitration caused by peroxynitrite had been observed in AD brains, a comparison of global gene profiles of UPS in NaHS-, nitric oxide- and lactacystin-treated neurons revealed a late transcriptional downregulation, indicating UPS dysfunction was a consequential outcome of H2S-induced neuronal... between H2S- and NMDA -mediated neuronal deaths v revealed involvement of identical signaling cascades, though the former initiated at a later time-point (15 h) than the latter (5 h) It could be speculated that H2S mediation of neuronal death converged to NMDA receptor signaling pathway, and that the delay in signaling as compared to direct induction of NMDA receptor by NMDA could be due to 2 possiblities:... of both NR1, and NR2 subunits, which comprise of any one of the four separate gene products (NR2A -D) The essentiality for the expression of both subunits arises from the formation of the glutamate 12 binding domain at the junction of NR1 and NR2 subunits Full activation of the NMDA receptors is achieved by the binding of glutamate and, glycine, a co-agonist binding on a site on NR1 subunit The binding... gene regulation profile during H2S -mediated neuronal death • To establish the association between NMDA receptors and H2S -mediated neuronal death through global gene profiles comparison between NMDA and H2S-induced deaths • To compare Ubiquitin-Proteasome System (UPS) gene profile of H2S-induced neuronal death with other modes of neuronal death: NO- and lactacystin 20 Chapter 2: Methodology 21 ... protection against glutamate -mediated excitotoxic neuronal death (Marini et al., 1998) Modest NMDA receptor activation also promotes neuronal survival in the forebrain neurons Application of exogenously NMDA attenuates neuronal death induced by staurosporine (Hardingham et al., 2002) or ethanol (Takadera and Ohyashiki, 2004) in cortical neurons On the other hand, addition of antagonists of NMDA receptors. .. potentiate N- methyl- D- aspartate (NMDA) receptor -mediated processes indirectly through events such as cAMP accumulation, thereby enhancing hippocampal long term potentiation Employing cultured murine primary cortical neurons with full expression of glutamate receptors and sodium hydrosulphide (NaHS) as a H2S donor, H2S is demonstrated to induce apoptotic-necrotic continuum in a dose- and timedependent... 2007) and maintenance of mitochondrial structure and function (Elrod et al., 2007) 8 1.1.4.3 Endocrine System Exogenously administered H2S and overexpression of CSE in rat insulinoma cells (Yang et al., 2005) and mouse pancreatic islets (Kaneko et al., 2006) resulted in reduced glucose-induced insulin release from the cells Furthermore, high expressions of CSE and CBS are found in the pancreas, and in the... Gene expression profiles of genes encoding proteins involved in calcium homeostasis and binding in cultured day 7 mouse primary cortical neurons treated with 200 µM NaHS and NMDA respectively 69 Table 3.3.4 Gene expression profiles of genes encoding proteins involved in cell survival in cultured day 7 mouse primary cortical neurons treated with 200 µM NaHS and NMDA respectively 70 Table 3.3.5 Gene... expression profiles of genes encoding proteins involved in ubiquitinproteasome system (UPS) in cultured day 7 mouse primary cortical neurons treated with 200 µM NaHS and NMDA respectively 76 Table 3.3.7.1 Genes differentially expressed during neuronal treatment with 200 µM NaHS, 0.5 mM NOC-18 and 1 µM lactacystin 80 Table 3.3.8 Gene expression profiles of genes encoding water and ion channels associated with... AD (Doraiswamy, 2003; Hynd et al., 2004), dementia associated with Down syndrome (Scheuer et al., 1996) and Huntington’s disease (Arundine et al., 2004) Similarly, calpain activation (reviewed in Zatz & Starling, 2005; Carragher, 2006) and lysosomal dysfunction (Nixon et al., 2000; Bahr and Bendiske, 2002) are consistently observed in neurodegenerative diseases 15 1.4 Association between H2S and NMDA ... supervisors, Dr Steve Cheung Nam Sang of Department of Biochemistry, NUS, Prof Philip Moore of Department of Pharmacology, NUS and, Dr Deng Lih Wen of Department of Biochemistry, NUS for their invaluable... (KA) receptors 12 Metabotropic GluRs (mGluRs) 12 NMDA receptors: A major subfamily of GluR superfamily 12 1.3.1 Physiological roles of NMDA receptors 13 1.3.2 Patho-physiological role of NMDA receptors: ... Proposed signaling cascade of H2S-mediated signaling cascade 122 through NMDA receptor 4.3 Similarities and differences between H2S- and NMDA-mediated 126 neuronal deaths 4.4 Comparison of UPS