Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss of bone substance is a common manifestation of hyperparathyroidism. This suggests that parathyroid hormone (PTH) plays an important role as to bone mass. To investigate the mechanism underlying this change in bone mass, I studied the effects of PTH on collagen synthesis and mitogenesis of UMR-106 rat osteoblastic osteosarcoma cells. PTH inhibits the mitogenesis of UMR-106 rat osteosarcoma cells, the half-maximal concentration being 10(-8) to 10(-7) M, which is similar to the EC50 for cyclic AMP accumulation. Cyclic AMP, whose intracellular concentration was increased by PTH, plays a role in the modulation of mitogenesis, as shown by the comparable inhibitory effects of 8-bromoadenosine-3',5'-cyclic AMP (10(-4) M), forskolin (10(-7) M), and the phosphodiesterase inhibitor, IBMX (10(-5) M). PTH, in a similar concentration range, directly inhibited collagen synthesis. Concurrent with the suppression of collagen synthesis, the amounts of a1(I) and a2(I) collagen mRNA decreased proportionately. The results show that PTH modulates collagen synthesis at the transcriptional level. I concluded that parathyroid hormone inhibits the mitogenesis of osteoblasts as well as collagen synthesis by these cells. The decreases in the number of osteoblasts and the amount of collagen synthesis contribute to the loss of bone substance in hyperparathyroidism.
 ...
PMID:The importance of parathyroid hormone in inhibition of collagen synthesis and mitogenesis of osteoblastic cell. 256 Jul 80

We investigated the presence and several of the properties of calmodulin in human parathyroid cells. Boiled extracts of such cell preparations contained a heat-stable factor causing a 2- to 3-fold calcium-dependent stimulation of calmodulin-deficient phosphodiesterase activity, which was parallel to that due to pure porcine calmodulin. This activation could be totally blocked by 10(-4) M trifluoperazine, with half-maximal inhibition at 3 X 10(-5) M, similar to the effects of this phenothiazine on porcine calmodulin. These results suggested the presence of calmodulin in human parathyroid cells. By comparison with known quantities of porcine calmodulin, human parathyroid cells contained 9-208 ng calmodulin/10(6) cells. The content of calmodulin in 3 normal parathyroid glands [65 +/- 8 (+/- SEM) ng/10(6) cells] did not differ significantly from that of 12 adenomas (61 +/- 16 ng/10(6) cells). Cells from 7 glands showing secondary hyperplasia, however, had significantly greater levels of calmodulin (164 +/- 11 ng/10(6) cells) than either normal cells or adenomas (P less than 0.001 and P less than 0.005, respectively). Extracts of human parathyroid cells caused half-maximal stimulation of phosphodiesterase activity at 1.1-4.8 microM free calcium. The concentrations of calcium half-maximally activating phosphodiesterase (Ka) did not differ significantly for normal or abnormal cells (3.3 +/- 0.03 vs. 2.6 +/- 0.33; P greater than 0.3). Moreover, in 2 cases in which normal parathyroid tissue was obtained from patients with adenomas, the Ka values for calcium for the normal and abnormal cells were similar (3.3 vs. 2.5 and 3.4 vs. 2.5 microM, respectively). Finally, there was no significant correlation between either the content of calmodulin or the Ka for calcium and the set-point for calcium [the calcium concentration causing half-maximal inhibition of parathyroid hormone (PTH) release] or the maximal rate of PTH secretion for dispersed parathyroid cells. These results suggest that human parathyroid cells contain calmodulin, but provide no evidence for a role of this protein in the abnormal calcium-regulated PTH release in hyperparathyroidism.
 ...
PMID:Calmodulin in dispersed human parathyroid cells. 627 Jan 80

Parathyroid hormone (PTH) is secreted from the parathyroid glands in response to low plasma calcium levels. Besides its classical actions on bone and kidney, PTH may have other important effects, including metabolic effects, as suggested for instance by increased prevalence of insulin resistance and type 2 diabetes in patients with primary hyperparathyroidism. Moreover, secondary hyperparathyroidism may contribute to the metabolic derangements that characterize states of vitamin D deficiency. PTH has been shown to induce adipose tissue lipolysis, but the details of the lipolytic action of PTH have not been described. Here we used primary mouse adipocytes to show that intact PTH (1-84) as well as the N-terminal fragment (1-37) acutely stimulated lipolysis in a dose-dependent manner, whereas the C-terminal fragment (38-84) was without lipolytic effect. The lipolytic action of PTH was paralleled by phosphorylation of known protein kinase A (PKA) substrates, i.e. hormone-sensitive lipase (HSL) and perilipin. The phosphorylation of HSL in response to PTH occurred at the known PKA sites S563 and S660, but not at the non-PKA site S565. PTH-induced lipolysis, as well as phosphorylation of HSL at S563 and S660, was blocked by both the PKA-inhibitor H89 and the adenylate cyclase inhibitor MDL-12330A, whereas inhibitors of extracellular-regulated kinase (ERK), protein kinase B (PKB), AMP-activated protein kinase (AMPK) and Ca(2+)/calmodulin-dependent protein kinase (CaMK) had little or no effect. Inhibition of phosphodiesterase 4 (PDE4) strongly potentiated the lipolytic action of PTH, whereas inhibition of PDE3 had no effect. Our results show that the lipolytic action of PTH is mediated by the PKA signaling pathway with no or minor contribution of other signaling pathways and, furthermore, that the lipolytic action of PTH is limited by simultaneous activation of PDE4. Knowledge of the signaling pathways involved in the lipolytic action of PTH is important for our understanding of how metabolic derangements develop in states of hyperparathyroidism, including vitamin D deficiency.
...
PMID:Parathyroid hormone induces adipocyte lipolysis via PKA-mediated phosphorylation of hormone-sensitive lipase. 2672 18