Document Detail

Protein kinase C and the opposite regulation of sodium channel alpha- and beta1-subunit mRNA levels in adrenal chromaffin cells.
MedLine Citation:
PMID:  10501224     Owner:  NLM     Status:  MEDLINE    
Our previous [3H]saxitoxin binding and 22Na influx assays showed that treatment of cultured bovine adrenal chromaffin cells with 12-O-tetradecanoylphorbol 13-acetate (TPA) or phorbol 12,13-dibutyrate (PDBu), an activator of protein kinase C (PKC), decreased the number of cell surface Na channels (IC50 = 19 nM) but did not alter their pharmacological properties; Na channel down-regulation developed within 3 h, reached the peak decrease of 53% at 15 h, and was mediated by transcriptional/translational events. In the present study, treatment with 100 nM TPA lowered the Na channel alpha-subunit mRNA level by 34 and 52% at 3 and 6 h, followed by restoration to the pretreatment level at 24 h, whereas 100 nM TPA elevated the Na channel beta1-subunit mRNA level by 13-61% between 12 and 48 h. Reduction of alpha-subunit mRNA level by TPA was concentration-dependent (IC50 = 18 nM) and was mimicked by PDBu but not by the biologically inactive 4alpha-TPA; it was prevented by H-7, an inhibitor of PKC, but not by HA-1004, a less active analogue of H7, or by H-89, an inhibitor of cyclic AMP-dependent protein kinase. Treatment with cycloheximide, an inhibitor of protein synthesis, per se sustainingly increased the alpha-subunit mRNA level and decreased the beta1-subunit mRNA level for 24 h; also, the TPA-induced decrease of alpha-subunit mRNA and increase of beta1-subunit mRNA were both totally prevented for 24 h by concurrent treatment with cycloheximide. Nuclear run-on assay showed that TPA treatment did not alter the transcriptional rate of the alpha-subunit gene. A stability study using actinomycin D, an inhibitor of RNA synthesis, revealed that TPA treatment shortened the t(1/2) of alpha-subunit mRNA from 18.8 to 3.7 h. These results suggest that Na channel alpha- and beta-subunit mRNA levels are differentially down- and up-regulated via PKC; the process may be mediated via an induction of as yet unidentified short-lived protein(s), which may culminate in the destabilization of alpha-subunit mRNA without altering alpha-subunit gene transcription.
T Yanagita; H Kobayashi; R Yamamoto; Y Takami; H Yokoo; T Yuhi; T Nakayama; A Wada
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of neurochemistry     Volume:  73     ISSN:  0022-3042     ISO Abbreviation:  J. Neurochem.     Publication Date:  1999 Oct 
Date Detail:
Created Date:  1999-10-14     Completed Date:  1999-10-14     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1749-57     Citation Subset:  IM    
Department of Pharmacology, Miyazaki Medical College, Kiyotake, Japan.
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MeSH Terms
Adrenal Medulla / metabolism*
Cell Nucleus / metabolism
Cells, Cultured
Chromaffin Cells / metabolism*
Cycloheximide / pharmacology
Down-Regulation / drug effects
Enzyme Activation
Gene Expression Regulation*
Macromolecular Substances
Phorbol 12,13-Dibutyrate / pharmacology
Protein Kinase C / metabolism*
RNA, Messenger / genetics
Sodium Channels / genetics*,  metabolism
Tetradecanoylphorbol Acetate / pharmacology
Transcription, Genetic*
Reg. No./Substance:
0/Macromolecular Substances; 0/RNA, Messenger; 0/Sodium Channels; 16561-29-8/Tetradecanoylphorbol Acetate; 37558-16-0/Phorbol 12,13-Dibutyrate; 66-81-9/Cycloheximide; EC Kinase C

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