Neurabin/protein phosphatase-1 complex regulates dendritic spine morphogenesis and maturation.
The majority of excitatory synapses in the mammalian brain form on filopodia and spines, actin-rich membrane protrusions present on neuronal dendrites. The biochemical events that induce filopodia and remodel these structures into dendritic spines remain poorly understood. Here, we show that the neuronal actin- and protein phosphatase-1-binding protein, neurabin-I, promotes filopodia in neurons and nonneuronal cells. Neurabin-I actin-binding domain bundled F-actin, promoted filopodia, and delayed the maturation of dendritic spines in cultured hippocampal neurons. In contrast, dimerization of neurabin-I via C-terminal coiled-coil domains and association of protein phosphatase-1 (PP1) with neurabin-I through a canonical KIXF motif inhibited filopodia. Furthermore, the expression of a neurabin-I polypeptide unable to bind PP1 delayed the maturation of neuronal filopodia into spines, reduced the synaptic targeting of AMPA-type glutamate (GluR1) receptors, and decreased AMPA receptor-mediated synaptic transmission. Reduction of endogenous neurabin levels by interference RNA (RNAi)-mediated knockdown also inhibited the surface expression of GluR1 receptors. Together, our studies suggested that disrupting the functions of a cytoskeletal neurabin/PP1 complex enhanced filopodia and impaired surface GluR1 expression in hippocampal neurons, thereby hindering the morphological and functional maturation of dendritic spines.
Terry-Lorenzo
Ryan T
RT
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Roadcap
David W
DW
Otsuka
Takeshi
T
Blanpied
Thomas A
TA
Zamorano
Pedro L
PL
Garner
Craig C
CC
Shenolikar
Shirish
S
Ehlers
Michael D
MD
D000199:Actins / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000235:genetics; D049229:Dendritic Spines / Q000378:metabolism* / Q000648:ultrastructure*; D019281:Dimerization; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D010749:Phosphoprotein Phosphatases / Q000737:chemistry / Q000378:metabolism*; D054645:Protein Phosphatase 1; D017434:Protein Structure, Tertiary; D011554:Pseudopodia / Q000378:metabolism / Q000648:ultrastructure; D034622:RNA Interference; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission; D014162:Transfection; D000099273:Neurabins
D000199:Actins; D018076:DNA, Complementary; D049452:Green Fluorescent Proteins; D008840:Microfilament Proteins; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D018091:Receptors, AMPA; D011993:Recombinant Fusion Proteins; D000099273:Neurabins
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