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    
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.
Michael D Carrithers; Gouri Chatterjee; Lisette M Carrithers; Roosevelt Offoha; Uzoma Iheagwara; Christoph Rahner; Morven Graham; Stephen G Waxman
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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    
Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06520-8018, USA.
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MeSH Terms
Alternative Splicing*
Calcium / metabolism
Cell Differentiation / drug effects
Cell Line, Tumor
Cell Membrane Structures / metabolism*
Macrophages, Peritoneal / metabolism*,  pathology
Melanoma / metabolism*,  pathology
Mice, Mutant Strains
Mitochondria / metabolism
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
K02 NS047457-05/NS/NINDS NIH HHS
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

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

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