Abstract
Rap1 is a small GTPase that has been implicated in dendritic development and plasticity. In this study, we investigated the role of Rap1 in axonal growth and its activation in response to neurotrophins and myelin-associated inhibitors. We report that Rap1 is activated by brain-derived neurotrophic factor and that this activation can be blocked by myelin-associated glycoprotein (MAG) or central nervous system myelin, which also induced increases in Rap1GAP1 levels. In addition, we demonstrate that adenoviral overexpression of Rap1 enhances neurite outgrowth in the presence of MAG and myelin, while inhibition of Rap1 activity through overexpression of Rap1GAP1 blocks neurite outgrowth. These findings suggest that Rap1GAP1 negatively regulates neurite outgrowth, making it a potential therapeutic target to promote axonal regeneration.
Keywords:
Axonal regeneration; MAG; Rap1; Rap1GAP1; myelin; small GTPase.
© 2020 Federation of European Biochemical Societies.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Brain-Derived Neurotrophic Factor / pharmacology
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Bucladesine / pharmacology
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Cyclic AMP / analogs & derivatives
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Cyclic AMP / pharmacology
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GTP Phosphohydrolases / genetics
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GTP Phosphohydrolases / metabolism*
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GTPase-Activating Proteins / metabolism
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Guanine Nucleotide Exchange Factors / metabolism
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Myelin Sheath / metabolism
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Myelin-Associated Glycoprotein / metabolism*
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Nerve Tissue Proteins
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Neuronal Outgrowth / drug effects
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Neuronal Outgrowth / physiology*
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Rats, Long-Evans
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Thionucleotides / pharmacology
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rap GTP-Binding Proteins / genetics
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rap GTP-Binding Proteins / metabolism
Substances
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1B236 polypeptide
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2'-O-methyl-8-(4-chlorophenylthio)cAMP
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Brain-Derived Neurotrophic Factor
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GTPase-Activating Proteins
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Guanine Nucleotide Exchange Factors
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Myelin-Associated Glycoprotein
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Nerve Tissue Proteins
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Rapgef3 protein, rat
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Thionucleotides
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Bucladesine
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Cyclic AMP
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GTP Phosphohydrolases
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rap GTP-Binding Proteins