Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

While protein kinase C (PKC) appears to play a role in the action of PTH in renal cells, direct evidence of activation by PTH is lacking. Rat PTH (1-34) caused a rapid, transient translocation of PKC in opossum kidney (OK) cells from a basal value of 0.09 to maximum of 0.24 at 10-15 sec. Both the time course and dose-response relationship of translocation matched a corresponding increase in cytosolic Ca2+. In contrast, PTH activation of cAMP-dependent protein kinase (PKA), while also rapid, was greater in magnitude (0.10 to 0.50), persistent, and occurred at a threshold level of 3 x 10(-10)M PTH, compared to 10(-8)M for PKC. Neither bPTH(3-34) nor bPTH(7-34) activated either protein kinase, while both antagonized rPTH(1-34)-induced PKC translocation more effectively than PKA activation. These differential effects of PTH agonist and antagonists further support the suggestion that PTH acts through two signal transduction mechanisms in which one or more receptors is linked in distinct ways to adenylate cyclase and phospholipase C.
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PMID:Parathyroid hormone 1-34, but not 3-34 or 7-34, transiently translocates protein kinase C in cultured renal (OK) cells. 293 May 65

Late passage cultures of a clonal osteogenic sarcoma line (ROS 17/2.8) failed to respond to PTH with activation of cAMP-dependent protein kinase isoenzymes despite showing a sensitive and dose-dependent increase in cAMP after treatment with the hormone. When cells were treated with hydrocortisone or dexamethasone, protein kinase responsiveness to PTH was readily demonstrated; such treatment also resulted in enhanced cAMP production. Forskolin preincubation resulted in a cAMP response to PTH of similar magnitude to that seen with hydrocortisone but no activation of cAMP-dependent protein kinase occurred. Thus, the effect of glucocorticoid cannot be explained merely by the increased amplitude and sensitivity of the cAMP response which developed with glucocorticoid treatment in these cells. The data indicate that cellular activation of cAMP-dependent protein kinase does not automatically follow cAMP generation and that information transfer can be restored by pharmacological means.
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PMID:Glucocorticoid treatment facilitates cyclic adenosine 3',5'-monophosphate-dependent protein kinase response in parathyroid hormone-responsive osteogenic sarcoma cells. 300 48

Parathyroid hormone is the most important calcium regulating hormone, especially in the process of aging. As a compensation for progressive calcium deficiency in aging, PTH secretion progressively rises. Heterogeneity of PTH in peripheral blood indicates the importance of understanding the degradation mechanism throughout the life cycle of the hormone. In addition to cathepsin B and D which degrades PTH in the liver, kidney and parathyroid gland, a new neutral PTH ase was found in the cytosolic fraction of rat kidney cells. PTH responsive bone and kidney cell lines, UMR-106 and OK cells, were found to degrade PTH by a chymotrypsin-like enzyme on the plasma membrane through a receptor mediated mechanism. This process was inhibited by cyclic AMP-A-kinase system and augmented by C-kinase system, suggesting an intimate relationship between PTH action and degradation and also a new physiological significance of PTH degradation.
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PMID:Parathyroid hormone--quo vadis? 307 69

Recombinant rat (Ra) and murine (Mu) immune interferons (IFN-gamma) were found to be phosphorylated by bovine heart muscle cAMP-dependent protein kinase at a single site, in contrast to human (Hu) IFN-gamma, which was reported to be phosphorylated at two different serine residues. Chromatography of a Staphylococcal aureus V8 protease digest of Ra or MuIFN-gamma indicated that the site of phosphorylation was in the carboxy-terminal undecamer fragment of the protein. Due to inherent problems in measuring both phenylthiohydantoin-serine (PTH-serine) and PTH-phosphoserine with an automated sequenator, a novel approach, involving partial Edman degradation of aliquots of the peptide followed by high performance liquid chromatography (HPLC) analysis, was developed. It was determined that Ser132 is the exclusive site of phosphorylation for both IFNs.
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PMID:Recombinant rat and murine immune interferons are phosphorylated at a single site, Ser132. 313 88

We have identified two protein kinase activities in homogenates of bovine parathyroid tissue following fractionation on DEAE columns. One of these is a protein kinase C based upon its requirement for calcium and phosphatidylserine and the other one is probably M kinase. The protein kinase C phosphorylated both proparathyroid hormone and parathyroid hormone but not secretory protein-I (SP-I). Neither N [1-34] or C [35-84] terminal hormonal fragments were phosphorylated, suggesting that the structure of the intact PTH molecule is required for recognition by the enzyme. A second kinase activity behaving like M kinase was also obtained. This activity, which was not separable from a cAMP dependent kinase, was maximal with only 50 mM MgCl2 as cofactor. SP-I was readily phosphorylated by this activity but parathyroid hormone was not.
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PMID:Protein kinase activities in the parathyroid gland: proparathyroid hormone, parathyroid hormone and secretory protein-I as substrates for phosphorylation. 320 46

The development of refractoriness of the cAMP response to PTH in primary cultures of chick kidney cells and recovery from the refractory state was investigated. When cells were preincubated with bovine PTH1-34, complete refractoriness to a subsequent challenge with the hormone developed within 2 h and at hormone concentrations as low as 5 ng/ml. The ability of PTH to stimulate activation of cAMP-dependent protein kinase was also abolished by preincubation with the hormone. When cells were desensitized and then incubated in hormone-free medium, recovery of the cAMP response began within an hour and was maximal, but not complete (80%) after 16 h. Cycloheximide did not affect either desensitization or the rate or extent of recovery from the refractory state. Low concentrations of forskolin (2.5 X 10(-7) M) greatly enhanced cAMP production stimulated by PTH and higher concentrations (10(-6) - 10(-4) M) stimulated rates of cAMP production 50 times those obtained with PTH alone. Preincubation with forskolin did not bring about desensitization to PTH nor did preincubation with PTH affect the subsequent response to forskolin. The half-life of biologically active bovine PTH1-34 in chick kidney cell culture was approximately 12 h and the rate of its removal was not significantly altered during a 20-h incubation period. The results suggest that desensitization of chick kidney cells to PTH is not suggest that desensitization of chick kidney cells to PTH is not brought about by cAMP generation itself, is not primarily dependent on protein synthesis, and does not involve a change in the rate of removal of biologically active hormone from the medium. In addition, recovery of the cAMP response to PTH also does not require new protein synthesis. These results are compatible with a mechanism of desensitization which occurs at the level of the receptor or hormone-receptor coupling to adenyl cyclase.
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PMID:Homologous desensitization of cultured chick kidney cells to parathyroid hormone. 631 38

PTH causes dose dependent transient vasodilatation in various vascular beds, specifically renal, coeliac, coronary, but not osseous. It has an acute dose-dependent hypotensive effect in the intact animal which is not mediated by alpha- or beta-adrenergic, cholinergic or histaminergic mechanisms. Aortic medial smooth muscle cells respond to PTH with an increase of cAMP, cGMP and, presumably via protein kinase, with activation of phosphorylase B kinase. The acute vasodilatory effect of PTH is antagonised by indomethacin and diclofenac as well as by ouabain, suggesting that the membrane Na-K pump and prostaglandins are involved in PTH-induced vasodilatation. Parathyroidectomy and a high calcium diet attenuate the rise of arterial pressure in experimental hypertension, pointing to some permissive effect of PTH for development hypertension. This is most likely due to long term effects of PTH on vessel wall calcium content and exchange. This chronic effect of PTH may explain the high prevalence of hypertension in patients with primary hyperparathyroidism.
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PMID:Vascular effects of parathyroid hormone (PTH). 675 27

Although PTH is known to stimulate both the adenylate cyclase/protein kinase-A system and the phospholipase-C/protein kinase-C second messenger systems, the relative roles of these second messenger pathways remain unclear. The present studies were designed to examine the effect of triamcinolone on PTH-stimulated second messenger systems and phosphate transport in confluent cultures of opossum kidney cells. Triamcinolone was added to these cultures at a concentration of 10 nM for 24-48 h. Neither cell number nor protein content was changed by this treatment. The addition of triamcinolone did not alter PTH receptor binding or competitive displacement radioligand binding assay curves. PTH-stimulated cAMP generation and activation of protein kinase-A were not altered by triamcinolone. The glucocorticoid, however, increased basal phosphate uptake from 1.0 +/- 0.1 to 1.28 +/- 0.1 pmol/5 min.culture (P < 0.01). Phosphate transport was significantly decreased by PTH (0.01 nM) in the triamcinolone-treated cultures, but not in control cultures. Phosphate uptake in the presence of maximal doses of PTH was similar in both control and triamcinolone-treated cultures. Thus, the PTH-responsive component of phosphate transport was preserved, and the threshold dose for the effect of PTH was reduced after treatment with triamcinolone. Studies were then performed to evaluate the alternate second messenger pathway. In control cultures, PTH rapidly increased the level of diglyceride mass, as measured by diglyceride kinase assay, from 0.18 +/- 0.01 to a peak of 0.26 +/- 0.02 mol/100 mol total phospholipid (P < 0.002), 1 min after addition of the hormone. Triamcinolone pretreatment for 48 h, however, elevated the basal diglyceride levels, but the increase after the addition of PTH was totally abolished. The absence of an increase in diglyceride upon stimulation with PTH correlated with elimination of the PTH-stimulated increase in the activity of particulate protein kinase-C. Thus, in triamcinolone-treated cells, the effect of PTH on phosphate transport was preserved, and the threshold dose of PTH-induced alteration in phosphate transport was reduced in the absence of stimulation of this alternate second messenger pathway. These data show that triamcinolone in opossum kidney cells does not alter PTH activation of the cAMP/protein kinase-A system, but eliminates the increase in diglyceride and the activation of protein kinase-C in response to PTH. These studies emphasize the major role of the protein kinase-A system in the regulation of phosphate transport by PTH.
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PMID:Effect of triamcinolone on parathyroid hormone-stimulated second messenger systems and phosphate transport in opossum kidney cells. 750 8

Available data indicate that adipocytes are targets for PTH action, and chronic excess of PTH increases calcium burden of fat tissue, suggesting that PTH increases entry of calcium into adipocytes. The present study examined the effects of PTH-(1-84) and its amino-terminal fragment, PTH-(1-34), on cytosolic calcium ([Ca2+]i) of adipocytes and evaluated the cellular pathways that mediate the potential effect of PTH on [Ca2+]i of these cells. PTH-(1-84) but not PTH-(1-34) produced a dose-dependent rise in [Ca2+]i of adipocytes. This effect occurred in the presence or absence of calcium in the media, but the magnitude of the rise in [Ca2+]i was significantly greater when calcium was present in the media. The PTH antagonist [Nle8,18Tyr34]bPTH(7-34)NH2, verapamil, and nifedipine blocked to variable degrees the PTH-induced rise in [Ca2+]i. The phorbol ester 12-O-tetradecanoyl phorbol-13-acetate, and the GTP-binding protein (G protein) GTP gamma S also produced a dose-dependent rise in [Ca2+]i of adipocytes. These effects were inhibited by staurosporine and the G protein inhibitor guanosine 5'-O-1(2-thiodiphosphate), respectively. Similary, staurosporine, calphostin C, guanosine 5'-O-1(2-thiodiphosphate), and pertussis toxin inhibited the effect of PTH on [Ca2+]i of adipocytes. (Bu)2cAMP also increased [Ca2+]i of adipocytes, but PTH did not stimulate cAMP production by adipocytes, and N-[2(p-bromocin-namylamino)ethyl]5-isoquinoline-sulfonamide, an inhibitor of protein kinase A, did not affect the PTH-induced rise in [Ca2+]i of adipocytes. The data indicate that: 1) PTH-(1-84) increases [Ca2+]i of adipocytes; 2) this action of the hormone is receptor mediated; 3) the hormone uses a G protein activation of calcium channels and the phospholipase C pathway in mediating its action on [Ca2+]i; and 4) the rise in [Ca2+]i is due to both increased calcium influx into the adipocytes and mobilization of calcium from intracellular stores.
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PMID:Effects of parathyroid hormone on cytosolic calcium of rat adipocytes. 752 54

PTH-related peptide (PTHrP), which shares 8 of 13 NH2-terminal residues with PTH, causes similar biological effects and interacts with the same receptor as PTH. In the gastrointestinal tract, human PTH and PTHrP-(1-34) relax rat fundic strips. However, the level of their action and the receptor involved in this effect are unknown. The aims of this study were 1) to determine the effects of human PTH-(1-34), human PTHrP-(1-34), -(1-16), and -(7-34) and vasoactive intestinal peptide (VIP) on circular isolated smooth muscle cells from guinea pig ileum; 2) to study the intracellular pathways involved in these effects; and 3) and to characterize the receptors involved by using specific antagonists. Smooth muscle cells were dispersed by enzymatic digestion. Contraction was assessed by measuring the length of 50 cells and expressed as the percent decrease in cell length from the control value. The relaxing effects of PTH, PTHrP and analogs, VIP, or antagonists were expressed as a percentage of the maximal effect observed in their absence. VIP, PTH-(1-34), and PTHrP-(1-34), -(1-16), and -(7-34) had no effect by themselves on these cells. However, when cells were contracted by the sulfated C-terminal octapeptide of cholecystokinin (10 nM), VIP, PTH-(1-34), and PTHrP(1-34) inhibited the sulfated C-terminal octapeptide of cholecystokinin-induced contraction in a concentration-dependent manner, whereas PTHrP-(1-16) and -(7-34) had no effect. The EC50 values of VIP, PTH-(1-34), and PTH-(1-34), and PTHrP-(1-34) were 7 nM, 20 pM, and 20 pM, respectively. The VIP antagonist ([D-P-Cl-Phe6,Leu17]VIP) inhibited VIP-, PTH-(1-34)-, and PTHrP(1-34)-induced relaxation, with IC50 values of 20, 500, and 400 pM, respectively. Likewise, the PTH/PTHrP antagonist [Tyr34-bovine PTH-(7-34)NH2] inhibited PTH-(1-34)-, PTHrP(1-34)-, and VIP-induced relaxation, with IC50 values of 1, 1, and 90 pM, respectively. Preincubation of cells with somatostatin, N-ethylmaleimide, and (R)-p-cyclic adenosine-3',5'-monophosphothioate inhibited the PTH-(1-34), PTHrP(1-34)-, and VIP-induced relaxation. In conclusion, human PTH and PTHrP induce a relaxation of intestinal smooth muscle by a direct myogenic effect. This effect requires the 1-34 amino acid sequence and is mediated by the activation of adenylate cyclase and protein kinase-A. Interactions among PTH, PTHrP, and VIP indicate that they may cross-react with their respective receptors.
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PMID:Parathyroid hormone (PTH) and PTH-related peptide induce relaxation of smooth muscle cells from guinea pig ileum: interaction with vasoactive intestinal peptide receptors. 752 62


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