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  • Title: Inactivation of atrial natriuretic factor-stimulated cyclic guanosine 3',5'-monophosphate (cGMP) in UMR-106 osteoblast-like cells.
    Author: Ahlström M, Lamberg-Allardt C.
    Journal: Biochem Pharmacol; 2000 May 01; 59(9):1133-9. PubMed ID: 10704943.
    Abstract:
    Previous studies have suggested a role of cyclic guanosine 3', 5'-monophosphate (cGMP) in the differentiation and proliferation of osteoblasts. We studied the effect of ANF (atrial natriuretic factor) on intracellular cGMP accumulation, cGMP efflux, and cGMP-phosphodiesterase (PDE) activity in UMR-106 osteoblast-like cells. ANF rapidly increased both intracellular cGMP and cGMP efflux. ANF-stimulated intracellular cGMP peaked at 2 min in the absence and at 10 min in the presence of 0.25 mM 3-isobutyl-1-methylxanthine. Probenecid, an antagonist of anion transport, blocked the efflux of cGMP (IC(50) = 0.1 mM), ruling out simple diffusion as a mechanism of the efflux. cGMP-PDE activity was increased threefold in crude homogenates from ANF-treated cells (IC(50) = 23 nM). ANF-evoked stimulation of cGMP-PDE activity was reached simultaneously with the peak in intracellular cGMP. Separation of the PDEs by Q-Sepharose chromatography revealed three cGMP-hydrolyzing peaks. The first peak was sensitive to the PDE5 (cGMP-specific PDE) isoenzyme-selective inhibitor zaprinast (IC(50) = 0.45 microM). The second peak was stimulated fourfold by the addition of calcium/calmodulin, indicating the presence of PDE1. The third peak was sensitive to the PDE2 (cGMP-stimulated PDE) isoenzyme-selective inhibitor 9-[2-hydroxy-3-nonyl]adenine (EHNA) (IC(50) = 3 microM), and was activated by over 300% in the presence of 4 microM cGMP. Our results show that ANF-stimulated cGMP is released from UMR-106 cells by a probenecid-sensitive mechanism. ANF also stimulates cGMP hydrolysis by activating cGMP-PDE activity. Three distinct cGMP-hydrolyzing PDEs, namely PDE5, PDE1, and PDE2, are present in the studied cells.
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