title: T-type Ca2+ channels are required for enhanced sympathetic axon growth by TNFα reverse signalling.
abstract: Tumour necrosis factor receptor 1 (TNFR1)-activated TNFα reverse signalling, in which membrane-integrated TNFα functions as a receptor for TNFR1, enhances axon growth from developing sympathetic neurons and plays a crucial role in establishing sympathetic innervation. Here, we have investigated the link between TNFα reverse signalling and axon growth in cultured sympathetic neurons. TNFR1-activated TNFα reverse signalling promotes Ca2+influx, and highly selective T-type Ca2+channel inhibitors, but not pharmacological inhibitors of L-type, N-type and P/Q-type Ca2+channels, prevented enhanced axon growth. T-type Ca2+channel-specific inhibitors eliminated Ca2+spikes promoted by TNFα reverse signalling in axons and prevented enhanced axon growth when applied locally to axons, but not when applied to cell somata. Blocking action potential generation did not affect the effect of TNFα reverse signalling on axon growth, suggesting that propagated action potentials are not required for enhanced axon growth. TNFα reverse signalling enhanced protein kinase C (PKC) activation, and pharmacological inhibition of PKC prevented the axon growth response. These results suggest that TNFα reverse signalling promotes opening of T-type Ca2+channels along sympathetic axons, which is required for enhanced axon growth.
authors.affiliation: School Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK.
authors.forename: Lilian
authors.initials: L
authors.lastname: Kisiswa
authors.affiliation: School Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK.
authors.forename: Clara
authors.initials: C
authors.lastname: Erice
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Andrew Huxley Building, Gower Street, London WC1E 6BT, UK.
authors.forename: Laurent
authors.initials: L
authors.lastname: Ferron
authors.affiliation: School Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK.
authors.forename: Sean
authors.initials: S
authors.lastname: Wyatt
authors.affiliation: School Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK.
authors.forename: Catarina
authors.initials: C
authors.lastname: Osório
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Andrew Huxley Building, Gower Street, London WC1E 6BT, UK.
authors.forename: Annette C
authors.initials: AC
authors.lastname: Dolphin
authors.affiliation: School Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK daviesalun@cf.ac.uk.
authors.forename: Alun M
authors.identifier: 0000-0001-5841-8176
authors.initials: AM
authors.lastname: Davies
mesh_terms: D000200:Action Potentials; D000818:Animals; D001369:Axons / Q000378:metabolism*; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D002478:Cells, Cultured; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D020747:Calcium Channels, T-Type; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D011493:Protein Kinase C
keywords: Ca2+ channels; TNFα; axon growth; development; reverse signalling; sympathetic neuron