RRC ID 12064
Author Takekoshi K, Ishii K, Shibuya S, Kawakami Y, Isobe K, Nakai T.
Title Stimulation of catecholamine biosynthesis via the protein kinase C pathway by endothelin-1 in PC12 rat pheochromocytoma cells.
Journal Biochem Pharmacol
Abstract It has been reported that endothelins (ETs) stimulate catecholamine release from chromaffin cells. However, it is not known whether ETs also affect catecholamine biosynthesis. Thus, using a rat pheochromocytoma cell line, PC12, we examined the effects of ETs on catecholamine biosynthesis. The mRNA level and activity of tyrosine hydroxylase (TH), a rate-limiting enzyme in catecholamine biosynthesis, were increased significantly by endothelin-1 (ET-1) (100nM). These stimulatory effects were inhibited completely by a blocker for the A-type endothelin receptor, BQ-123 [cyclo(D-alpha-aspartyl-L-prolyl-D-valyl-L-leucyl-D-tryptophyl)] (1 microM), but not by a blocker for the B-type endothelin receptor, BQ-788 (N-cis 2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D-1-methoxycarbonyltryptophanyl-D-norleucine (1 microM). Also, Ro-32-0432 (3-[8-[(dimethylamino)methyl]-6,7,8,9-tetrahydropyrido-[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-H-pyrrole-2,5-dione hydrochloride) (100nM), a protein kinase C inhibitor, completely inhibited ET-1-induced increases in TH activity and mRNA level. Furthermore, ET-1 (100nM) significantly stimulated protein kinase C activity, as well as inositol 1,4,5-triphosphate production; these stimulatory effects were abolished by BQ-123 but not by BQ-788. Moreover, ET-1 (100nM) significantly increased both the TH-protein level and the intracellular catecholamine content. By contrast to ET-1, endothelin-3 did not affect catecholamine synthesis. These results indicate that ET-1, but not ET-3, stimulates catecholamine synthesis through the PKC pathway in PC12 cells. Also, the use of selective ET receptor antagonists suggests that the effects of ET-1 on catecholamine biosynthesis are mediated through ET(A).
Volume 63(5)
Pages 977-84
Published 2002-3-1
DOI 10.1016/s0006-2952(01)00862-0
PII S0006295201008620
PMID 11911850
MeSH Animals Catecholamines / biosynthesis* Cyclic AMP / metabolism Endothelin-1 / pharmacology* Endothelin-3 / pharmacology* Inositol 1,4,5-Trisphosphate / metabolism PC12 Cells Pheochromocytoma / pathology Protein Kinase C / drug effects Protein Kinase C / metabolism* RNA, Messenger / drug effects RNA, Messenger / metabolism Rats Tumor Cells, Cultured Tyrosine 3-Monooxygenase / drug effects Tyrosine 3-Monooxygenase / genetics Tyrosine 3-Monooxygenase / metabolism*
IF 4.96
Times Cited 6
DNA material pHTH1 Human tyrosine hydroxylase type I cDNA (RDB1269)
Human and Animal Cells PC-12(RCB0009)