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Investigating the Mechanisms of Action of VGF-Derived Peptides in the Nervous System

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Investigating the Mechanisms of Action of VGF-Derived Peptides in the Nervous System Investigating the mechanisms of action of VGF-derived peptides in the nervous system Mahmood Ayub A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy ( Ph.D. ) of Imperial College London January 2012 Imperial College London Department of Life Sciences Division of Cell and Molecular Biology 1 Abstract The VGF neurosecretory protein, first identified as a nerve growth factor (NGF) inducible gene product, is selectively synthesised predominantly in neuronal and neuroendocrine cells. The ~68 kDa VGF protein sequence is rich in paired basic amino acids, and thus the protein undergoes endoproteolytic cleavage to produce smaller peptides, which are stored in dense core vesicles and released upon stimulation via the regulated secretory pathway both in vitro and in vivo . Several of these VGF-derived peptides have been characterised and are involved in energy homeostasis, reproductive processes, synaptic plasticity as well as pain modulation. A number of studies have observed an increase in VGF gene expression in various pain models and more recently the VGF-derived peptides, TLQP-21, LQEQ-19 and TLQP-62 showed direct modulation of inflammatory and neuropathic pain when applied in vivo . The molecular mechanisms of action of VGF-derived peptides are not well understood and were investigated in this study. The TLQP-21 peptide, but not LQEQ-19, was shown to dose-dependently induce an increase in intracellular Ca 2+ levels from cellular internal stores in brain- and spinal cord-derived primary microglia, in >65 % of the cell population in vitro . Three hour treatment of primary microglia with TLQP-21 (100 nM) induced a 2.78 fold increase in Ccl11 and a 2.28 fold decrease in Cxcl9 gene expression levels relative to the vehicle control (Student's t-test; p ≤ 0.05). Biochemical analysis using affinity chromatography and LC-MS/MS techniques identified the gC1q-R protein as a potential binding partner / receptor for TLQP-21. The gC1q-R protein is a ubiquitously expressed, multi-compartmental protein involved in complement activation, inflammatory processes and the plasma bradykinin formation pathway. These results tentatively suggest that TLQP-21 may contribute to the modulation of pain through activation of primary microglia and potentially involve interactions with components of the complement system. The findings highlight the importance of VGF-derived peptides in pain research and could lead to new perspectives and targets for pain therapeutics. 2 Declaration of Originality I hereby declare that the work described in this thesis is the result of my own independent investigation, unless otherwise stated. Any information derived from the published and unpublished work of others has been acknowledged in the text and a list of references is given in the bibliography. This work is not the same as any that I have submitted for a degree, diploma or other qualification at any other university. Mahmood Ayub 3 Table of Contents Abstract ........................................................................................................................ 2 Declaration of Originality ........................................................................................... 3 Table of Contents ........................................................................................................ 4 List of Figures and Tables .......................................................................................... 8 Acknowledgements .................................................................................................... 10 Selected Abbreviations .............................................................................................. 11 CHAPTER 1: GENERAL INTRODUCTION ...................................................13 Introduction ............................................................................................................... 14 Pain ....................................................................................................................................................14 Definitions and classification ........................................................................................................14 Dorsal Root Ganglia (DRG)- neurons and nociception .................................................................15 Glia, immune cells and pain ..........................................................................................................16 i. Microglia and pain modulation .............................................................................................19 Calcium (Ca 2+ ) signalling .................................................................................................................21 Ca 2+ cell compartments .................................................................................................................22 Ca 2+ channels and transporters ......................................................................................................24 Ca 2+ signalling in neurons and glia ................................................................................................26 VGF: An inducible gene product ....................................................................................................27 Identification of an NGF inducible gene .......................................................................................27 Structure of the vgf gene ................................................................................................................28 The VGF precursor and VGF-derived peptides.............................................................................29 i. The VGF precursor protein ...................................................................................................29 ii. VGF-derived peptides ...........................................................................................................30 Expression and distribution of VGF and VGF-derived peptides ...................................................33 Functions of VGF ..........................................................................................................................35 i. VGF knockout mice ...............................................................................................................35 ii. Role(s) of VGF in energy homeostasis .................................................................................36 iii. VGF peptides and water balance ........................................................................................38 iv. Role of VGF peptides in reproduction .................................................................................38 v. VGF functions in the gastrointestinal tract ...........................................................................39 vi. VGF in hippocampal function and behaviour ......................................................................39 vii. VGF as a neuroprotective agent .........................................................................................40 viii. VGF as a biomarker in disease states ...............................................................................41 ix. VGF in pain signalling and modulation ..............................................................................42 Aims ............................................................................................................................ 44 CHAPTER 2: INVESTIGATING THE EFFECTS OF VGF-DERIVED PEPTIDES ON INTRACELLULAR CA 2+ LEVELS ........................................45 Introduction ............................................................................................................... 46 Methods for studying Ca 2+ signalling .............................................................................................46 VGF and pain modulation ...............................................................................................................49 Aims ...................................................................................................................................................51 4 Materials & Methods ................................................................................................ 52 VGF-derived peptides ......................................................................................................................52 Primary DRG culture ......................................................................................................................52 Primary microglia culture ...............................................................................................................53 ND7, BHK and BV-2 cell culture ....................................................................................................54 Fluo-4AM cell loading, confocal imaging and analysis .................................................................55 Statistical analysis ............................................................................................................................56 Results ........................................................................................................................ 57 Investigating the effects of intracellular Ca 2+ levels on cells following application of VGF- derived peptides ................................................................................................................................57 The TLQP-21 peptide induces an increase in intracellular Ca 2+ levels in microglia, in
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