Tonic ATP-mediated growth suppression in peripheral nerve glia requires arrestin-PP2 and is evaded in NF1
Autor: | Craig S. Thomson, Lindsey Aschbacher-Smith, Katherine E. Chaney, Michael P. Jankowski, Nancy Ratner, Li Guo, Robert A. Coover, Tabitha E. Healy, Robert F. Hennigan |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Schwann Purinergic lcsh:RC346-429 Mice Adenosine Triphosphate Ganglia Spinal Hydroxides Neurofibroma Protein Phosphatase 2 Receptor Cells Cultured Pain Measurement Neurons Arrestin Neurofibromin 1 Chemistry Purinergic receptor Cell cycle Bupivacaine Sciatic Nerve Cell biology PP2A Neuroglia Sodium Channel Blockers Mice Transgenic Tetrodotoxin Pathology and Forensic Medicine Neurofibromatosis 03 medical and health sciences Cellular and Molecular Neuroscience P2Y2 Glia medicine Animals Humans Protein kinase B lcsh:Neurology. Diseases of the nervous system Cell growth Research AKT Protein phosphatase 2 Embryo Mammalian medicine.disease ATP Mice Inbred C57BL 030104 developmental biology Calcium Neurology (clinical) Sciatic Neuropathy |
Zdroj: | Acta Neuropathologica Communications, Vol 6, Iss 1, Pp 1-15 (2018) Acta Neuropathologica Communications |
ISSN: | 2051-5960 |
DOI: | 10.1186/s40478-018-0635-9 |
Popis: | Normal Schwann cells (SCs) are quiescent in adult nerves, when ATP is released from the nerve in an activity dependent manner. We find that suppressing nerve activity in adult nerves causes SC to enter the cell cycle. In vitro, ATP activates the SC G-protein coupled receptor (GPCR) P2Y2. Downstream of P2Y2, β-arrestin-mediated signaling results in PP2-mediated de-phosphorylation of AKT, and PP2 activity is required for SC growth suppression. NF1 deficient SC show reduced growth suppression by ATP, and are resistant to the effects of β-arrestin-mediated signaling, including PP2-mediated de-phosphorylation of AKT. In patients with the disorder Neurofibromatosis type 1, NF1 mutant SCs proliferate and form SC tumors called neurofibromas. Elevating ATP levels in vivo reduced neurofibroma cell proliferation. Thus, the low proliferation characteristic of differentiated adult peripheral nerve may require ongoing, nerve activity-dependent, ATP. Additionally, we identify a mechanism through which NF1 SCs may evade growth suppression in nerve tumors. Electronic supplementary material The online version of this article (10.1186/s40478-018-0635-9) contains supplementary material, which is available to authorized users. |
Databáze: | OpenAIRE |
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