title: GSK3 and β-catenin determines functional expression of sodium channels at the axon initial segment.
abstract: Neuronal action potentials are generated through voltage-gated sodium channels, which are tethered by ankyrinG at the membrane of the axon initial segment (AIS). Despite the importance of the AIS in the control of neuronal excitability, the cellular and molecular mechanisms regulating sodium channel expression at the AIS remain elusive. Our results show that GSK3α/β and β-catenin phosphorylated by GSK3 (S33/37/T41) are localized at the AIS and are new components of this essential neuronal domain. Pharmacological inhibition of GSK3 or β-catenin knockdown with shRNAs decreased the levels of phosphorylated-β-catenin, ankyrinG, and voltage-gated sodium channels at the AIS, both "in vitro" and "in vivo", therefore diminishing neuronal excitability as evaluated via sodium current amplitude and action potential number. Thus, our results suggest a mechanism for the modulation of neuronal excitability through the control of sodium channel density by GSK3 and β-catenin at the AIS.
authors: Department of Cellular, Molecular and Developmental Neurobiology, Instituto Cajal, CSIC, Avenida Doctor Arce, Madrid, 28002, Spain.
authors: Mónica
authors: M
authors: Tapia
authors: Ana
authors: A
authors: Del Puerto
authors: Alberto
authors: A
authors: Puime
authors: Diana
authors: D
authors: Sánchez-Ponce
authors: Laure
authors: L
authors: Fronzaroli-Molinieres
authors: Noemí
authors: N
authors: Pallas-Bazarra
authors: Edmond
authors: E
authors: Carlier
authors: Pierre
authors: P
authors: Giraud
authors: Dominique
authors: D
authors: Debanne
authors: Francisco
authors: F
authors: Wandosell
authors: Juan José
authors: JJ
authors: Garrido
mesh_terms: D000200:Action Potentials; D000818:Animals; D017487:Ankyrins / Q000378:metabolism; D001369:Axons / Q000378:metabolism* / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D010766:Phosphorylation; D034622:RNA Interference; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism* / Q000502:physiology; D051176:beta Catenin / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: C094681:Ank3 protein, mouse; D017487:Ankyrins; D061566:Voltage-Gated Sodium Channels; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3