title: Functional Interaction between the Scaffold Protein Kidins220/ARMS and Neuronal Voltage-Gated Na+ Channels.
abstract: Kidins220 (kinase D-interacting substrate of 220 kDa)/ankyrin repeat-rich membrane spanning (ARMS) acts as a signaling platform at the plasma membrane and is implicated in a multitude of neuronal functions, including the control of neuronal activity. Here, we used the Kidins220(-/-) mouse model to study the effects of Kidins220 ablation on neuronal excitability. Multielectrode array recordings showed reduced evoked spiking activity in Kidins220(-/-) hippocampal networks, which was compatible with the increased excitability of GABAergic neurons determined by current-clamp recordings. Spike waveform analysis further indicated an increased sodium conductance in this neuronal subpopulation. Kidins220 association with brain voltage-gated sodium channels was shown by co-immunoprecipitation experiments and Na(+) current recordings in transfected HEK293 cells, which revealed dramatic alterations of kinetics and voltage dependence. Finally, an in silico interneuronal model incorporating the Kidins220-induced Na(+) current alterations reproduced the firing phenotype observed in Kidins220(-/-) neurons. These results identify Kidins220 as a novel modulator of Nav channel activity, broadening our understanding of the molecular mechanisms regulating network excitability.
authors.affiliation: Center for Synaptic Neuroscience, Istituto Italiano di Tecnologia, 16163 Genova, Italy. Electronic address: fabrizia.cesca@iit.it.
authors.forename: Fabrizia
authors.initials: F
authors.lastname: Cesca
authors.affiliation: Center for Synaptic Neuroscience, Istituto Italiano di Tecnologia, 16163 Genova, Italy; Department of Experimental Medicine, University of Genova, 16132 Genova, Italy.
authors.forename: Annyesha
authors.initials: A
authors.lastname: Satapathy
authors.affiliation: Center for Synaptic Neuroscience, Istituto Italiano di Tecnologia, 16163 Genova, Italy; Sensorimotor Group, German Primate Center, 37077 Göttingen, Germany.
authors.forename: Enrico
authors.initials: E
authors.lastname: Ferrea
authors.affiliation: Neuro Technology Department, Istituto Italiano di Tecnologia, 16163 Genova, Italy.
authors.forename: Thierry
authors.initials: T
authors.lastname: Nieus
authors.affiliation: Center for Synaptic Neuroscience, Istituto Italiano di Tecnologia, 16163 Genova, Italy; Department of Experimental Medicine, University of Genova, 16132 Genova, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Benfenati
authors.affiliation: Center for Synaptic Neuroscience, Istituto Italiano di Tecnologia, 16163 Genova, Italy; Institute of Biophysics, Consiglio Nazionale delle Ricerche, 16149 Genova, Italy. Electronic address: scholz@ge.ibf.cnr.it.
authors.forename: Joachim
authors.initials: J
authors.lastname: Scholz-Starke
mesh_terms: D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005071:Evoked Potentials; D017353:Gene Deletion; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009415:Nerve Net; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*
chemical_list: C544017:Kidins220 protein, mouse; D008565:Membrane Proteins; D061566:Voltage-Gated Sodium Channels
keywords: gating; hippocampus; neuron; patch clamp; scaffold protein; sodium channel