Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vitro studies on single microdissected segments have been extensively used during the 20 past years to localize V1 and V2 vasopressin receptors within the mammalian kidney, and define their role in the control of water balance. Based on vasopressin-dependent adenylate cyclase activity measurements and quantitative RT-PCR studies, it is now clear that V2 receptors are present along the whole collecting duct from cortex to papilla, and, in most species, in the ascending limb of Henle's loop (thick and thin limb); occasionally in the distal tubule but not in the other segments. The stimulation by cyclic AMP of sodium chloride reabsorption in the thick ascending limb, and of urea reabsorption in the papillary collecting duct indicates that vasopressin--in addition to its well known hydroosmotic effect--also participates in the building up of the corticopapillary gradient of osmotic pressure. As regards the V1a receptor, binding studies as well as quantitative RT-PCR, and measurements of free cytosolic calcium concentration allow us to draw the following conclusions. In the rat, the V1a receptor is absent from the glomerulus, the proximal tubule (convoluted and straight portions), the tick ascending limb of Henle's loop and the terminal portion of the papillary collecting duct. It is present in the thin ascending limb and the cortical and outer medullary portions of the collecting duct. Its presence in the thin descending limb has not, up to now, been explored. By contrast with previous data in the rabbit, the V1a receptor does not alter vasopressin-dependent sodium and water reabsorption in the rat cortical collecting duct. Further studies will be necessary to determine its functional role in that segment, as well as in the thin ascending limb. Finally, vasopressin V2 agonists have been shown to induce intracellular calcium release in the papillary collecting duct, a segment devoid of V1a receptors. This effect--which cannot be ascribed to a cross-reaction with oxytocic receptors--indicates either an unusual coupling of the V2 receptor to phospholipase C or, else, the presence of a new vasopressin receptor.
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PMID:[Functional expression of vasopressin receptors V1a and V2 along the mammalian nephron]. 859 Feb 15

PTH administration decreases proximal HCO3 reabsorption and inhibits the brush border Na-H antiporter. We studied the effect of PTH on the renal Na-HCO3 cotransporter and examined whether this effect is mediated through the adenylate cyclase/cyclic AMP system or through the phospholipase A pathway. We studied the effect of PTH [1-34] on the Na-HCO3 cotransporter activity in rabbit renal basolateral membranes incubated with 50 microM ATP by measuring the 22Na uptake in the presence of HCO3 and gluconate. Na-HCO3 cotransporter activity (expressed in nmol/mg protein/3 seconds) was taken as the difference in 22Na uptake in the presence of HCO3 and gluconate. PTH (10(-10) M) completely inhibited Na-HCO3 cotransporter activity from 1.23 +/- 0.14 to -0.58 +/- 0.23, P < 0.001. This effect of PTH to inhibit the Na-HCO3 cotransporter was prevented by the polyclonal antibody against G alpha s indicating that PTH acts through G alpha s protein. Because G alpha s stimulates adenylate cyclase/cyclic AMP system, we examined the effect of PTH in the presence and in the absence of the adenylate cyclase inhibitor, dideoxyadenosine (DDA). DDA alone (10(-4) M) stimulated the Na-HCO3 cotransporter activity. In the presence of DDA, the net inhibitory effect of PTH was the same magnitude as that of control, suggesting the existence of other pathways for the effect of PTH on the cotransporter. Calmodulin inhibition also partially prevented the effect of PTH. To determine whether the inhibitory effect of PTH is mediated at least in part, through phospholipase A, we first examined the effect of PTH on arachidonic acid release and then measured the Na-HCO3 cotransporter activity in presence and in absence of arachidonic acid or eicosatetraynoic acid (ETA), an inhibitor of arachidonic acid metabolism. PTH significantly increased the release of arachidonic acid by isolated proximal tubule cells and arachidonic acid inhibited the Na-HCO3 cotransporter in basolateral membranes. ETA (3 microM) partially prevented the inhibitory effect of PTH. In cultured proximal tubule cells, PTH inhibited the HCO3-dependent 22Na uptake and ethoxyresorufin, an inhibitor of cytochrome P-450, blocked the inhibitory effect of PTH on the cotransporter. These results demonstrate that PTH inhibits the renal Na-HCO3 cotransporter through multiple mechanisms, that are mediated through G proteins, G alpha s and GP, and CaM-KII.
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PMID:Regulation of the renal Na-HCO3 cotransporter: V. mechanism of the inhibitory effect of parathyroid hormone. 882 23

Using a micro-radioimmunoassay, cAMP was measured in single, isolated S2 proximal straight tubules dissected from rabbit kidneys to investigate the effects of adrenergic agonists on adenylate cyclase activity. The baseline activity of adenylate cyclase was low and unaffected by either the alpha 2 agonist clonidine, the beta agonist isoprenaline (in the absence or presence of 1 microM forskolin) or 1 microM forskolin. Adenylate cyclase activity was markedly stimulated by 20 microM forskolin, an effect which was inhibited by 1 microM clonidine. The inhibition by clonidine was not apparent in the presence of the alpha 2 antagonist yohimbine. These results confirm the inability of isoprenaline to stimulate adenylate cyclase in the rabbit proximal tubule and demonstrate the coupling of alpha 2 receptors, in an inhibitory fashion, to adenylate cyclase. The inhibitory action of the alpha 2-receptor agonist was independent of other hormone activity in the renal proximal tubule.
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PMID:Interaction between adrenergic agonists and forskolin on adenylate cyclase activity in the rabbit proximal tubule. 886 80

Among kidney tubular epithelial cell types, proximal tubule cells are one of the major renal targets for xenobiotics. Several in vitro culture models have been proposed for use of proximal tubule cells for in vitro pharmacotoxicology studies. This paper reports a comparative study of the response to cephaloridine exposure of two established cell lines from pig (LLC-PK1) and rabbit (LLC-RK1) kidneys and primary cultures of rat and rabbit proximal tubule cells. These cultured cells were first compared for their levels of activity of alpha-methylglucopyranoside transport, alkaline phosphatase, succinate dehydrogenase, and NADPH cytochrome c reductase, their glutathione-dependent activity levels, and their adenylate cyclase response pattern to stimulation by PTH and AVP. The results presented show major phenotypic differences between these four cellular models. The differences observed in glutathione-dependent mechanism activities and regulation may in part be responsible for the variability of the responses of these four cellular models when exposed to cephaloridine.
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PMID:Comparative impact of cephaloridine on glutathione and related enzymes in LLC-PK1, LLC-RK1, and primary cultures of rat and rabbit proximal tubule cells. 903 21

In the rabbit, calcitonin has been shown to enhance calcium (Ca2+) reabsorption in the early distal tubule. The aim of the present study was to investigate the mechanism of this action, using isolated luminal and basolateral membranes of distal tubules. The tubule suspensions were preincubated in the presence or absence of 10(-7) M calcitonin. The luminal or basolateral membranes were subsequently purified and 45Ca transport through the vesicles was measured using the rapid filtration technique. Results were compared with those obtained from proximal tubule membranes. In the proximal tubules, calcitonin had no effect on Ca2+ uptake by luminal membranes. In the distal tubules, the presence of Na+ in the incubation medium strongly decreased the uptake of Ca2+ by luminal membranes. Preincubation of distal tubules with calcitonin partially restored this uptake. We previously reported a dual kinetics of Ca2+ uptake by the distal luminal membranes. Calcitonin enhanced Ca2+ transport by the low affinity component, increasing the Vmax and leaving the K(m) unchanged. Renal calcitonin receptors usually couple to both adenylate cyclase and phospholipase C. To determine through which messenger(s) calcitonin enhances Ca2+ transport by the distal tubules, we first confirmed that the hormone stimulates cAMP and IP3 release. Incubation of the distal tubules with 10(-7) M calcitonin significantly increased both messengers. In contrast, calcitonin did not influence the IP3 nor the cAMP content of proximal tubules. Therefore, we studied the actions of cAMP and phorbol 12-myristate 13 acetate (PMA) on Ca2+ transport by the distal luminal membranes. Incubation of distal tubule suspensions with dibutyryl cAMP significantly increased Ca2+ uptake by the luminal membranes. However, incubation of these tubules with various concentrations of PMA (10 nM, 100 nM and 1 microM) had no effect on this uptake. Calcitonin also influenced Ca2+ transport by the distal basolateral membrane. Incubation of distal tubule suspensions with 10(-7) M calcitonin activated the Na+/Ca2+ exchanger activity, almost doubling the Na+ dependent Ca2+ uptake. Here again this action was mimicked by cAMP. We conclude that calcitonin increases Ca2+ transport by the distal tubule through two mechanisms: the opening of low affinity Ca2+ channels in the luminal membrane and the stimulation of the Na+/Ca2+ exchanger in the basolateral membrane, both actions depending on the activation of adenylate cyclase.
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PMID:Effect of calcitonin on calcium transport by the luminal and basolateral membranes of the rabbit nephron. 918 93

Several studies have demonstrated that the neonatal kidney has a markedly attenuated response to parathyroid hormone (PTH); however, the cause for this blunted response is unknown. PTH stimulated cAMP production by 215 +/- 18% in neonatal proximal tubule suspensions compared to a 35 +/- 7% increase in adult proximal tubules. Thus, neonatal proximal tubules have functioning PTH receptors and a greater adenylate cyclase response than the adult segment. In adult proximal tubules, PTH stimulates phospholipase A2 (PLA2) activity and the inhibition of Na,K-ATPase activity by PTH is blocked by inhibitors of PLA2. We examined whether maturational changes in renal cortical activity could play a role in the attenuated response to PTH in the neonatal proximal tubule. Compared to adults, neonates had a lower renal cortical cytosolic PLA2 (cPLA2) activity, assessed as the release of 14C-arachidonic acid (AA) from labeled phosphatidyl choline (0.44 +/- 0.10 vs. 0.74 +/- 0.06% 14C-AA released/min/mg protein, P < 0.05) and microsomal PLA2 activity (0.32 +/- 0.03 vs. 1.20 +/- 0.13% 14C-AA released/min/mg protein, P < 0.001). The protein abundance of cPLA2 was not different between the neonatal and adult renal cortex as assessed by immunoblot assay. Thus, the difference in activities must be due to a difference in regulation of cPLA2. Annexin 1 (lipocortin 1) has been shown to inhibit PLA2 activity by binding to phospholipid substrate. Annexin 1 protein abundance was higher in neonatal than in adult renal cortex (P < 0.001). Thus, the lower activity of PLA2 in the neonatal tubules may be due in part to higher expression of annexin 1. PLA2 activation by PTH, -8-bromo-cAMP and PMA was assessed as 3H-AA release from prelabeled suspensions of neonatal and adult proximal tubules. PTH (10(-7) M), 8-bromo-cAMP (10(-4) M) and PMA (5 x 10(-8) M) significantly increased 3H-AA release from adult tubules (P < 0.05) but had no effect on neonatal tubules (P = NS). Thus, PTH, 8-bromo-cAMP and PMA stimulated PLA2 in adult but not neonatal proximal tubules. In conclusion, the maturational changes in renal cortical PLA2 activity may be a factor in the blunted response of neonatal proximal tubules to PTH.
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PMID:Maturational changes in rabbit renal cortical phospholipase A2 activity. 921 48

After collagenase digestion and Percoll density gradient centrifugation of human renal tissue, tubular epithelial cells of the proximal and the distal segments were isolated with an immunomagnetic method using MACS microbeads. To enrich proximal tubular (PT) cells we used a monoclonal antibody (mAb) against aminopeptidase M (APM, CD 13), specific of the proximal tubule. Distal tubular (DT) cells were isolated through a mAb recognizing Tamm-Horsfall glycoprotein (THG), a specific antigen for the thick ascending limb and the early distal convoluted tubule. Cells of the proximal primary isolate were histochemically strongly positive for aminopeptidase M (98.6%), however, cells of the distal portion were negative (98.7%). Ultrastructural analysis of PTC primary isolates revealed highly preserved brush border microvilli, well-developed endocytosis apparati and numerous mitochondria, whereas DTC primary isolates showed smaller cells with basolateral invaginations and less apical microvilli. Characterization by immunofluorescence indicated the coexpression of cytokeratin and vimentin, whereas staining for desmin, smooth muscle actin, a fibroblast-specific marker and von Willebrand factor was negative. Cultured PT and DT cells displayed different adenylate cyclase responsiveness to hormonal stimulation. PTH (10(-6) M) increased cAMP production in distal cells up to 32.8-fold of the basal level and in proximal only up to 3.5-fold (10(-8) M, DT 14.4x and PT 2.25x). Calcitonin stimulated adenylate cyclase in DT in a dose dependent fashion (10(-6) M, 4.3x; 10(-8) M, 2.25x), whereas only a low calcitonin response was found in PT cells (10(-6) M, 1.6x; 10(-8) M, 1.4x). AVP (10(-6) M) activated the distal cAMP-production only up to 1.9x of the basal level, but the proximal cAMP-production was negligible (only 1.3x the basal level). The data of this study indicate the proximal and distal tubule origin of the cultured cells that were isolated according to their segment-specific antigens.
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PMID:Isolation of proximal and distal tubule cells from human kidney by immunomagnetic separation. Technical note. 935 Jun 55

The present study was performed to characterize the possible involvement of cAMP synthesis and protein kinase C (PKC) activation in the DNA synthesis-stimulating effect of parathyroid hormone-related protein (PTHrP) in proximal tubule cells. We found that DNA synthesis was stimulated by 10 microM 8BrcAMP, and 1 microM Sp-cDBIMPS, two cAMP analogs, and also by 1 microM phorbol 12-myristate 13-acetate (PMA) and 100 microM 1,2-dioctanoyl-sn-glycerol, two PKC activators, and 10 nM [Cys23] human (h)PTHrP (24-35) amide in rabbit proximal tubule cells (PTC). Both Sp-cDBIMPS and PMA, at 1 microM, also increased DNA synthesis in SV40-immortalized mouse proximal tubule cells MCT. Human PTHrP (7-34) amide [PTHrP (7-34)] dose dependently stimulated DNA synthesis in a similar manner as [34Tyr]PTHrP (1-34) amide [PTHrP (1-34)], in PTC. PMA pre-treatment for 20 h, which downregulates PKC, completely blocked the effect induced by PTHrP (7-34), but not that of PTHrP (1-34), in the latter cells. In contrast, the same PMA pre-treatment abolished the DNA synthesis stimulation by PTHrP (1-34) and PTHrP (7-34) in MCT cells, which appear to have PTH receptors mainly coupled to phospholipase C and not adenylate cyclase. Our results indicate that the stimulatory effect of PTHrP on DNA synthesis in proximal tubule cells is mediated by a cAMP- and PKC-dependent mechanism.
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PMID:Parathyroid hormone-related protein increases DNA synthesis in proximal tubule cells by cyclic AMP- and protein kinase C-dependent pathways. 965 Nov 15

The renal functional changes following infusion of dopamine are well documented. The most pronounced effect is the increase in renal blood flow and a marked natriuretic response. Due to its specific renal effects, dopamine has become one of the most frequently used drugs in the treatment of critically ill patients with low cardiac output states and/or acute oliguric renal failure. Pharmacological effects of dopamine are dose dependent. Low doses of dopamine predominantly stimulate dopaminergic receptors, but with increasing doses actions secondary to stimulation of adrenergic beta(1) and alpha receptors also appear. Dopamine receptors are classified into the D1 and the D2 subtype families. Stimulation of D1 receptors increases adenylate cyclase activity and intracellular levels of cAMP, whereas D2 receptor activation decrease or do not change adenylate cyclase activity. In the kidney, dopamine receptors have been localized in the renal vasculature except in glomeruli and in the tubules (the proximal tubule > macula densa > the loop of Henle > the distal tubule > collecting ducts). The postsynaptic D1 receptor mediates vasodilation by a direct mechanism, whereas the presynaptic D2 receptor indirectly may dilate the vessels by inhibition of norepinephrine release. Consistent with previous results in animals, the present haemodynamic studies revealed that dopamine in normal subjects elicits a dose dependent biphasic effect on the mean arterial blood pressure. With 1 and 2 micrograms/kg/min, a depressor effect resulted from a decrease in the diastolic pressure, whereas a pressor effect, seen with doses at and above 7.5 micrograms/kg/min, was mainly caused by elevations of the systolic pressure. The studies indicated that the increase in cardiac output at low doses of dopamine is secondary to a decrease in peripheral vascular resistance, independent of effects of beta(1) receptors on cardiac contractility and heart rate. Dose-response studies demonstrated that the dopamine-induced increase in effective renal plasma flow (ERPF) reaches its maximum at 3 micrograms/kg/min. The increase in ERPF remained unchanged by pretreatment with metoprolol, and a comparison of dopamine and dobutamine in doses producing similar increases in cardiac output demonstrated that only dopamine increased ERPF. These findings indicate that indirect haemodynamic effects secondary to increases in cardiac contractility and cardiac output do not contribute significantly to the increase in renal perfusion caused by dopamine. In normal subjects, acute hypoxaemia attenuated the renal vasodilating effect of dopamine. The well known natriuretic effect of dopamine was significantly expressed in all of our studies, in which doses ranging from 1 to 5 micrograms/kg/min caused about a two-fold increase in sodium excretion. At doses at and above 7.5 micrograms/kg/min which increased mean arterial pressure, dopamine further increased sodium clearance (CNa) while ERPF was decreasing, indicating the contribution of pressure natriuresis at these high doses. Although not affecting the percentage increase in CNa, metoprolol suppressed the absolute, maximal response to non-pressor doses of dopamine, suggesting that a reduced adrenergic beta(1) receptor activity may indirectly affect the natriuretic response, probably by decreasing renal perfusion pressure. Previous studies in animals demonstrated that dopamine natriuresis can occur independent of increases in ERPF and GFR, and, furthermore, that the response can be abolished by specific D1 receptor antagonists. Evidence obtained by in vitro studies indicated that dopamine via D1 receptors may inhibit the Na(+)-H+ antiport at the brush-border membrane of proximal tubular cells and the Na(+)-K(+)-ATPase activity at basolateral membranes of both the proximal tubule and the medullary thick ascending limb of the loop of Henle. (ABSTRACT TRUNCATED)
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PMID:Effects of dopamine on renal haemodynamics tubular function and sodium excretion in normal humans. 967 40

Previous studies have documented that the vasoactive agonist angiotensin II (AngII) directly affects proximal tubular sodium-bicarbonate reabsorption in a biphasic manner, whereby picomolar concentrations promote reabsorption and nanomolar concentrations have the converse effect. Although it is generally agreed that the AT1 receptor subtype mediates AngII-induced sodium-bicarbonate reabsorption primarily through adenylate cyclase, the receptor subtype mediating natriuresis is less well defined. Using mouse proximal tubular cells, this study documents AT1-dependent enhancement (candesartan-inhibitable) of bicarbonate reabsorption and AT2-induced (PD123319- and CGP42112A-inhibitable) decrement of bicarbonate absorption. The signaling mechanisms were examined in rabbit proximal tubule cells in culture. The AT2 signaling involves G protein beta- and gamma-mediated phospholipase A2 activation, arachidonic acid release, and downstream events linked to Shc/Grb2/Sos and p21ras rather than protein kinase C as reported previously for AngII receptors. These observations provide a novel mechanism for AngII-AT2 receptor-mediated transport modulation.
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PMID:Renal proximal tubular AT2 receptor: signaling and transport. 989 43


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