ISSN:
0730-2312
Keywords:
cation-sensing receptor
;
BoPCaR
;
diacyglycerol
;
gadolinium
;
fluoroaluminate
;
de nove bone formation
;
Life and Medical Sciences
;
Cell & Developmental Biology
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
Notes:
Alumminium (Al3+) stimulates de novo bono formation in dogs and is a potent stimulate for DNA synthesis in non-transformed osteoblast in vitro. The recent identification of a G-protein couplked cation-sensing recepector(BoPCaR), which is activated by polycalant agonists [e.g., gadolinium (Gd3+) 〉 neomycin 〉 calcium(CA3+)], suggests that a similer physiologically inportant cation sensing receptor may be presant in obsoblasts and pharmacologically activated by Al3+. To evalute that possibility, we assessed whether known as BoPCaR agonists on DNA synthesis in a dose-dependent fashion, achiving 50% effective extracelluler concennetration (EC50) of 10 μM, 30 μM, 60 μM, and 2.5 mM, respectively. Al3+ displayed non-additive effect on DNA sunthesis with the BoPCAaR agonists as well as an unrelated G-porotien coupled receptor agonists, PGF2α, suggesting shared mechenisms of action. In contrast, the recepator tyrosine kinse agonist, IGF-1(10 ηg/ml), displayed additive proliferative effects when comboined with AlCl3, inducating distinct signalling pathways. AlCl3 (25 μM) induced DAG levels 2-fold and the phosphorylation of the myristoylated alanine-rich C kinase (MARKS) substrates 4-fold, but did not increase intracelluler calcium concenitrations. Doen-regardation of PKC by pre-treatment with phorbol 12-myristate 13-acetate as well as PKC inhebitation by H-7 and staurosporine blocked Al3+ -inducing DNA synthesis. Finally, Al3+, Gd3+, nemomycin, and Ca2+ activated G-proteins inn osteoblast membrans as evidenced by increased colvant binding pf [32P]-GTP-azidoanilide to putaitve Gα subunits. Our findings suggests that Al3+ stimulates DNA synthesis in ostoblasts through a cation sansing mechnism coupled to G-protein activation and signalling cascades involvings DAG and PCK- dependent pathways.
Additional Material:
5 Ill.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1002/jcb.240560115
