title: Filamin A promotes dynamin-dependent internalization of hyperpolarization-activated cyclic nucleotide-gated type 1 (HCN1) channels and restricts Ih in hippocampal neurons.
abstract: The actin-binding protein filamin A (FLNa) regulates neuronal migration during development, yet its roles in the mature brain remain largely obscure. Here, we probed the effects of FLNa on the regulation of ion channels that influence neuronal properties. We focused on the HCN1 channels that conduct Ih, a hyperpolarization-activated current crucial for shaping intrinsic neuronal properties. Whereas regulation of HCN1 channels by FLNa has been observed in melanoma cell lines, its physiological relevance to neuronal function and the underlying cellular pathways that govern this regulation remain unknown. Using a combination of mutational, pharmacological, and imaging approaches, we find here that FLNa facilitates a selective and reversible dynamin-dependent internalization of HCN1 channels in HEK293 cells. This internalization is accompanied by a redistribution of HCN1 channels on the cell surface, by accumulation of the channels in endosomal compartments, and by reduced Ih density. In hippocampal neurons, expression of a truncated dominant-negative FLNa enhances the expression of native HCN1. Furthermore, acute abrogation of HCN1-FLNa interaction in neurons, with the use of decoy peptides that mimic the FLNa-binding domain of HCN1, abolishes the punctate distribution of HCN1 channels in neuronal cell bodies, augments endogenous Ih, and enhances the rebound-response ("voltage-sag") of the neuronal membrane to transient hyperpolarizing events. Together, these results support a major function of FLNa in modulating ion channel abundance and membrane trafficking in neurons, thereby shaping their biophysical properties and function.
authors.affiliation: From the Departments of Anatomy/Neurobiology and Pediatrics and.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Noam
authors.forename: Markus U
authors.initials: MU
authors.lastname: Ehrengruber
authors.forename: Annie
authors.initials: A
authors.lastname: Koh
authors.forename: Paul
authors.initials: P
authors.lastname: Feyen
authors.forename: Erik M M
authors.initials: EM
authors.lastname: Manders
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Abbott
authors.forename: Wytse J
authors.initials: WJ
authors.lastname: Wadman
authors.forename: Tallie Z
authors.initials: TZ
authors.lastname: Baram
mesh_terms: D000818:Animals; D034281:Dynamins / Q000235:genetics / Q000378:metabolism*; D064448:Filamins / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics / Q000378:metabolism*; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C578663:FLNA protein, human; D064448:Filamins; C529499:FlnA protein, mouse; C578665:HCN1 protein, human; C578666:Hcn1 protein, mouse; C578667:Hcn1 protein, rat; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels; D034281:Dynamins
keywords: Actin; Endocytosis; Filamin A; HCN; Ih; Ion Channels; Neurons; Trafficking