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Voltage-Gated Ca2+ Channels and Their Regulation by Alternative Splicing

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Voltage-Gated Ca2+ Channels and Their Regulation by Alternative Splicing Trafficking of N-type voltage-gated Ca2+ channels and their regulation by alternative splicing Natsuko Macabuag Doctor of Philosophy UCL 2015 Department of Neuroscience, Physiology and Pharmacology Division of Biosciences Andrew Huxley Building University College London Gower Street London WC1E 6BT I, Natsuko Macabuag confirm that the work presented in this thesis is my own. Where information is derived from other sources, I confirm that this has been indicated in this thesis. Natsuko Macabuag - 2 - Abstract N-type voltage-gated calcium (CaV2.2) channels are expressed predominantly in the central and peripheral nervous systems and play a crucial role in neurotransmitter release. Expression of these channels at the plasma membrane and in the membrane of presynaptic terminals is key for their function, however, how they are trafficked from the subcellular organelles is still poorly understood. In this study, trafficking of mutually-exclusive alternative splice variants of CaV2.2, containing either exon 37a or 37b at the proximal C- terminus and its mechanisms were examined. CaV2.2 with exon 37a (selectively expressed in nociceptors) reveals a significantly greater intracellular trafficking to the axons and plasma membrane of DRG neurons than CaV2.2 with exon 37b. Further examination of the amino acid sequence in exon 37 uncovers that the canonical binding motifs for adaptor protein 1 (AP-1), YxxΦ and [DE]xxxL[LI], present only in exon 37a are accountable for mediating the enhanced channel trafficking from the trans-Golgi network to the plasma membrane. Finally, the dopamine-2 receptor (D2R) and its agonist-induced activation, reveal differential effects on trafficking of these CaV2.2 isoforms. D2R slowed the endocytosis of CaV2.2 containing exon 37b but not exon 37a, and activation by the D2R-selective agonist quinpirole reversed the effect of the D2R. Disrupting the interaction between adaptor proteins and YxxΦ or [DE]xxxL[LI] in CaV2.2 perturbed these effects, suggesting that the interaction of adaptor proteins with CaV2.2 channels may also be key underlying mechanisms for differential trafficking of CaV2.2 splice variants, mediated by D2R. This study thus reveals key mechanisms involved in the trafficking of N-type calcium channels. - 3 - Acknowledgement First and foremost, I would like to thank my supervisor Professor Annette Dolphin who has been very supportive throughout my PhD, and given me scientific advice and guidance by providing me tremendous insight and knowledge into the subject. I would also like to thank all the present and past Dolphin lab members for giving me practical and technical advice whenever I needed it. All the scientific and non-scientific discussions we shared in the lab and during lunchtimes will always be fond memories of my PhD that will stay with me. Last but not least, I would like to thank my family for supporting me throughout the PhD, especially my loving husband Josh Macabuag for encouraging me to study for my PhD. Without him, I might not be writing this acknowledgement of my PhD thesis – so thank you. Dolphin lab members (present and past) Annette Dolphin, Laurent Ferron, Manuela Nieto-Rostro, Karen Page, Ivan Kadurin, Marianna D’Arco, Shehrazade Dahimene, Wendy Pratt, Kanchan Chaggar, Wojciech Margas, Simon Rothwell, Stuart Martin, Beatrice Lana, John Cassidy, Otto Mayer, Susy Senatore, Claudia Bauer Natsuko Macabuag - 4 - Publication Macabuag, N. and Dolphin, A.C. (2015). Alternative splicing in CaV2.2 regulates neuronal trafficking via adaptor protein complex-1 adaptor protein motifs. The Journal of Neuroscience. 2015 Oct 28; 35(43):14636-52. doi: 10.1523/JNEUROSCI.3034-15.2015. - 5 - Table of Contents Chapter 1 Introduction ......................................................................................... 18 1.1 Background ...................................................................................... 18 1.1.1 Neurons .................................................................................... 18 1.1.2 Plasma membrane and membrane potential ............................. 18 1.1.3 Ion channels .............................................................................. 19 1.1.4 Action potential .......................................................................... 20 1.1.5 Neurotransmitter release ........................................................... 20 1.2 Voltage-gated calcium ion channels (VGCCs).................................. 22 1.2.1 CaV2.2 (N-type) ......................................................................... 25 1.2.2 Structure of CaV2.2 .................................................................... 25 1.2.3 G-protein-mediated regulation of VGCCs .................................. 30 1.3 Alternative splicing ........................................................................... 31 1.3.1 Alternative splicing in VGCCs .................................................... 31 1.3.2 Expression of CaV2.2e37a/b ...................................................... 37 2+ 1.3.3 CaV2.2e37a channels conduct more Ca current than e37b ..... 39 1.3.4 CaV2.2e37a/b undergo different modes of inhibition upon GPCR activation …………………………………………………………………………39 1.3.5 Roles of CaV2.2e37a/b in neuropathic pain ............................... 40 1.4 Protein sorting to and from plasma membrane ................................. 41 1.4.1 Trans-Golgi Network (TGN) to plasma membrane..................... 43 1.4.2 Plasma membrane to endosomes ............................................. 45 1.4.3 Recycling endosome pathways ................................................. 48 1.5 VGCC trafficking mechanisms and regulations ................................ 49 1.5.1 Auxiliary subunits ...................................................................... 49 1.5.2 Cytosolic proteins ...................................................................... 49 1.5.3 GPCRs ...................................................................................... 50 1.6 Hypothesis ....................................................................................... 51 1.7 Aim .................................................................................................. 53 Chapter 2 Materials and Methods........................................................................ 54 2.1 cDNA constructs .............................................................................. 54 2.2 Antibodies ........................................................................................ 57 2.3 Molecular biology ............................................................................. 59 - 6 - 2.3.1 Polymerase-chain reaction (PCR) ............................................. 59 2.3.2 Restriction digests ..................................................................... 66 2.3.3 Gel electrophoresis ................................................................... 67 2.3.4 Ligation ..................................................................................... 68 2.3.5 Transformation .......................................................................... 68 2.3.6 Clone selection .......................................................................... 68 2.3.7 Plasmid cDNA purification ......................................................... 69 2.3.8 Sequencing ............................................................................... 69 2.4 Cell culture and transfection ............................................................. 70 2.4.1 tsA-201 cell culture .................................................................... 70 2.4.2 N2a cell culture ......................................................................... 70 2.4.3 DRG neuronal cell culture ......................................................... 71 2.4.4 DRG-dorsal horn (DH) co-culture .............................................. 72 2.4.5 Hippocampal neuronal cell culture ............................................. 73 2.5 Western Blot .................................................................................... 74 2.5.1 Whole-cell proteins .................................................................... 74 2.5.2 Biotinylation of plasma membrane proteins ............................... 75 2.6 Visualisation of calcium ion channels ............................................... 75 2.6.1 Immunocytochemistry ............................................................... 75 2.6.2 Endocytosis assay ..................................................................... 76 2.6.3 Forward trafficking assay ........................................................... 76 2.6.4 Confocal microscopy ................................................................. 77 2.7 Electrophysiology ............................................................................. 78 2.8 Co-localisation analysis .................................................................... 79 2.9 Sample numbers .............................................................................. 80 2.10 Statistical analysis ............................................................................ 80 Chapter 3 Molecular tools to study trafficking of CaV2.2 splice variants ......... 81 3.1 Introduction ...................................................................................... 81 3.2 mEos-tagged CaV2.2 ........................................................................ 81 3.2.1 Biophysical properties of mEos-CaV2.2 splice variants .............. 82 3.2.2 Cellular localisation of mEos-tagged
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