title: Wnt5a inhibits K(+) currents in hippocampal synapses through nitric oxide production.
abstract: Hippocampal synapses play a key role in memory and learning processes by inducing long-term potentiation and depression. Wnt signaling is essential in the development and maintenance of synapses via several mechanisms. We have previously found that Wnt5a induces the production of nitric oxide (NO), which modulates NMDA receptor expression in the postsynaptic regions of hippocampal neurons. Here, we report that Wnt5a selectively inhibits a voltage-gated K(+) current (Kv current) and increases synaptic activity in hippocampal slices. Further supporting a specific role for Wnt5a, the soluble Frizzled receptor protein (sFRP-2; a functional Wnt antagonist) fully inhibits the effects of Wnt5a. We additionally show that these responses to Wnt5a are mediated by activation of a ROR2 receptor and increased NO production because they are suppressed by the shRNA-mediated knockdown of ROR2 and by 7-nitroindazole, a specific inhibitor of neuronal NOS. Together, our results show that Wnt5a increases NO production by acting on ROR2 receptors, which in turn inhibit Kv currents. These results reveal a novel mechanism by which Wnt5a may regulate the excitability of hippocampal neurons.
authors: Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Jorge
authors: J
authors: Parodi
authors: Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Carla
authors: C
authors: Montecinos-Oliva
authors: Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Talca, Chile.
authors: Rodrigo
authors: R
authors: Varas
authors: Fundación Ciencia y Vida, Santiago, Chile; Facultad de Ciencias Naturales y Exactas, Universidad de Playa Ancha, Valparaiso, Chile.
authors: Iván E
authors: IE
authors: Alfaro
authors: Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Felipe G
authors: FG
authors: Serrano
authors: Fundación Ciencia y Vida, Santiago, Chile.
authors: Manuel
authors: M
authors: Varas-Godoy
authors: Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Parc de Recerca Biomédica de Barcelonab, Spain.
authors: Francisco J
authors: FJ
authors: Muñoz
authors: Laboratorio de Función y Patología Neuronal, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, P. Universidad Católica de Chile, Santiago, Chile.
authors: Waldo
authors: W
authors: Cerpa
authors: Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile; Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Parc de Recerca Biomédica de Barcelonab, Spain.
authors: Juan A
authors: JA
authors: Godoy
authors: Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile; Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia; Centro UC Síndrome de Down, Pontificia Universidad Católica de Chile, Santiago, Chile; Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile. Electronic address: ninestrosa@bio.puc.cl.
authors: Nibaldo C
authors: NC
authors: Inestrosa
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000166:cytology*; D066298:In Vitro Techniques; D007191:Indazoles / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000502:physiology*; D014161:Transduction, Genetic; D051153:Wnt Proteins / Q000502:physiology*; D000071818:Wnt-5a Protein; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007191:Indazoles; D015221:Potassium Channels; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C491837:Wnt5a protein, rat; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; C500913:Ror2 protein, rat; D011188:Potassium; C080122:7-nitroindazole
keywords: Hippocampal neurons; K(+) current; ROR2 receptor; Wnt5a