Exchange Protein Directly Activated by cAMP (EPAC) Regulates Neuronal Polarization through Rap1B
| Autor: | Pablo Muñoz-Llancao, Felipe Bodaleo, Daniel R. Henríquez, Christian Gonzalez-Billault, Carlos Wilson, Erik Boddeke, Frank Lezoualc'h, Martina Schmidt |
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| Přispěvatelé: | Molecular Neuroscience and Ageing Research (MOLAR), Translational Immunology Groningen (TRIGR), Molecular Pharmacology, Groningen Research Institute for Asthma and COPD (GRIAC) |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
neuronal polarity
AXON INITIAL SEGMENT CYCLIC-AMP GTPase Rap1b signaling CELL-MIGRATION NEURITE OUTGROWTH Hippocampus Rats Sprague-Dawley Mice medicine KINASE Animals Guanine Nucleotide Exchange Factors Protein Isoforms Ankyrin EPAC signaling Axon Protein kinase A Neurons chemistry.chemical_classification axon biology HIPPOCAMPAL-NEURONS General Neuroscience Cell Polarity cytoskeleton Articles Axon initial segment Axons MEDIATED ACTIVATION Rats Cell biology rap GTP-Binding Proteins medicine.anatomical_structure DIFFERENTIATION chemistry nervous system Second messenger system PLASMA-MEMBRANE Synaptophysin biology.protein Guanine nucleotide exchange factor Neuroscience Signal Transduction POLARITY |
| Zdroj: | Journal of Neuroscience Artículos CONICYT CONICYT Chile instacron:CONICYT The Journal of Neuroscience, 35(32), 11315-11329. Oxford University Press |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | Acquisition of neuronal polarity is a complex process involving cellular and molecular events. The second messenger cAMP is involved in axonal specification through activation of protein kinase A. However, an alternative cAMP-dependent mechanism involves the exchange protein directly activated by cAMP (EPAC), which also responds to physiological changes in cAMP concentration, promoting activation of the small Rap GTPases. Here, we present evidence that EPAC signaling contributes to axon specification and elongation. In primary rat hippocampal neurons, EPAC isoforms were expressed differentially during axon specification. Furthermore, 8-pCPT, an EPAC pharmacological activator, and genetic manipulations of EPAC in neurons induced supernumerary axons indicative of Rap1b activation. Moreover, 8-pCPT-treated neurons expressed ankyrin G and other markers of mature axons such as synaptophysin and axonal accumulation of vGLUT1. In contrast, pharmacological inhibition of EPAC delayed neuronal polarity. Genetic manipulations to inactivate EPAC1 using either shRNA or neurons derived from EPAC1 knock-out (KO) mice led to axon elongation and polarization defects. Interestingly, multiaxonic neurons generated by 8-pCPT treatments in wild-type neurons were not found in EPAC1 KO mice neurons. Altogether, these results propose that EPAC signaling is an alternative and complementary mechanism for cAMP-dependent axon determination. SIGNIFICANCE STATEMENT This study identifies the guanine exchange factor responsible for Rap1b activation during neuronal polarization and provides an alternate explanation for cAMP-dependent acquisition of neuronal polarity. |
| Databáze: | OpenAIRE |
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