Document Detail


Regulation of podosome formation in macrophages by a splice variant of the sodium channel SCN8A.
MedLine Citation:
PMID:  19136557     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Voltage-gated sodium channels initiate electrical signaling in excitable cells such as muscle and neurons. They also are expressed in non-excitable cells such as macrophages and neoplastic cells. Previously, in macrophages, we demonstrated expression of SCN8A, the gene that encodes the channel NaV1.6, and intracellular localization of NaV1.6 to regions near F-actin bundles, particularly at areas of cell attachment. Here we show that a splice variant of NaV1.6 regulates cellular invasion through its effects on podosome and invadopodia formation in macrophages and melanoma cells. cDNA sequence analysis of SCN8A from THP-1 cells, a human monocyte-macrophage cell line, confirmed the expression of a full-length splice variant that lacks exon 18. Immunoelectron microscopy demonstrated NaV1.6-positive staining within the electron dense podosome rosette structure. Pharmacologic antagonism with tetrodotoxin (TTX) in differentiated THP-1 cells or absence of functional NaV1.6 through a naturally occurring mutation (med) in mouse peritoneal macrophages inhibited podosome formation. Agonist-mediated activation of the channel with veratridine caused release of sodium from cationic vesicular compartments, uptake by mitochondria, and mitochondrial calcium release through the Na/Ca exchanger. Invasion by differentiated THP-1 and HTB-66 cells, an invasive melanoma cell line, through extracellular matrix was inhibited by TTX. THP-1 invasion also was inhibited by small hairpin RNA knockdown of SCN8A. These results demonstrate that a variant of NaV1.6 participates in the control of podosome and invadopodia formation and suggest that intracellular sodium release mediated by NaV1.6 may regulate cellular invasion of macrophages and melanoma cells.
Authors:
Michael D Carrithers; Gouri Chatterjee; Lisette M Carrithers; Roosevelt Offoha; Uzoma Iheagwara; Christoph Rahner; Morven Graham; Stephen G Waxman
Related Documents :
17790657 - Ii. asynchronous flash initiation by a propagated triggering potential.
19195857 - Pinoresinol-4,4'-di-o-beta-d-glucoside from valeriana officinalis root stimulates calci...
3256447 - Secretion of intact pth by dispersed human hyperparathyroid cells.
7530837 - An experimental model of the production of early after depolarizations by injury curren...
21282747 - An easy method to highlight chief cells in gastric biopsies.
19543297 - Marine-derived oligosaccharide sulfate (jg3) suppresses heparanase-driven cell adhesion...
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-01-09
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  284     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2009 Mar 
Date Detail:
Created Date:  2009-03-16     Completed Date:  2009-05-14     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8114-26     Citation Subset:  IM    
Affiliation:
Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06520-8018, USA. carrithers@neurology.wisc.edu
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Alternative Splicing*
Animals
Calcium / metabolism
Cell Differentiation / drug effects
Cell Line, Tumor
Cell Membrane Structures / metabolism*
Exons
Humans
Macrophages, Peritoneal / metabolism*,  pathology
Melanoma / metabolism*,  pathology
Mice
Mice, Mutant Strains
Mitochondria / metabolism
Mutation
NAV1.6 Voltage-Gated Sodium Channel
Neoplasm Invasiveness
Nerve Tissue Proteins / metabolism*
Sodium Channel Blockers / pharmacology
Sodium Channels / metabolism*
Tetrodotoxin / pharmacology
Veratridine / pharmacology
Grant Support
ID/Acronym/Agency:
K02 NS047457-05/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/NAV1.6 Voltage-Gated Sodium Channel; 0/Nerve Tissue Proteins; 0/SCN8A protein, human; 0/Scn8a protein, mouse; 0/Sodium Channel Blockers; 0/Sodium Channels; 4368-28-9/Tetrodotoxin; 71-62-5/Veratridine; 7440-70-2/Calcium
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Different requirement for Rnd GTPases of R-Ras GAP activity of Plexin-C1 and Plexin-D1.
Next Document:  Inappropriate activation of cyclin-dependent kinases by the phosphatase Cdc25b results in premature ...