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)

1. Because in vitro adenylate cyclase activity studies suggest that parathyroid hormone (PTH) and calcitonin (CT) increase renal tubular calcium and magnesium reabsorption by stimulating the same transport mechanism, the separate and combined effects of these hormones on calcium and magnesium transport was assessed in the rat. 2. Fractional excretion of calcium was 9.5 +/- 0.5% in calcium-infused thyroparathyroidectomized (TPTX) rats and was reduced to 5.1 +/- 0.6 and 4.1 +/- 0.6% by maximal hypocalciuric concentrations of PTH and CT, respectively. 3. Combined administration of maximal PTH and CT produced an effect on fractional and absolute calcium excretion similar to that recorded with maximal CT alone. The combined administration of half-maximal concentrations of PTH and CT also produced a comparable fall in the fractional excretion of calcium to 3.0 +/- 0.7%, which was similar to that observed in the 'maximal CT' and 'maximal PTH plus CT' groups. The magnesium reabsorption data were comparable. 4. These results support biochemical data suggesting that PTH and CT act upon the same transport site, presumably within the thick ascending limb of Henle's loop, to facilitate calcium and magnesium reabsorption.
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PMID:Comparison of parathyroid hormone and calcitonin on rat renal calcium and magnesium transport. 160 45

A novel mutant of the LLC-PK1 renal epithelial cell line, VPR1, was isolated after mutagenesis with N-methyl-N'-nitro-N-nitrosoguanidine and selection using a photoactivatable vasopressin analogue [1-(3-mercapto)propionic acid, 8-(N6-4-azidophenylamidino)lysine] vasopressin. The VPR1 mutant cell line possessed less than 5% parental V2 receptor binding for vasopressin but exhibited normal calcitonin receptor binding. In contrast to LLC-PK1 cells (wild type), VPR1 cells exhibited no response to vasopressin in terms of in vitro adenylate cyclase activation, in vivo cAMP production, or urokinase-type plasminogen activator induction. The responses of VPR1 cells to other agents, such as calcitonin, the adenylate cyclase activator forskolin, the GTP analogue guanosine 5'-[beta, gamma-imino] triphosphate, 8-bromo adenosine-3',5'-monophosphate were comparable to those of the parental cell line. Somatic cell hybrids were derived from the cell lines LLC-PK1 and VPR1 and analyzed for the dominance/recessiveness of the VPR1 mutant phenotype. Hybrids were found to possess normal vasopressin binding activity as well as functional responses to the hormone, indicating that the mutation affecting the V2 receptor in VPR1 cells is recessive. The VPR1 cell line may thus have application as a recipient for the expression of the V2 receptor gene using DNA-transfer.
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PMID:Isolation and genetic characterization of a renal epithelial cell mutant defective in vasopressin (V2) receptor binding and function. 164 58

Membranes prepared from the medullary region of the porcine kidney displayed high affinity, high density (Kd, 0.12 nM; binding capacity, 127 fmol/mg protein) receptors for calcitonin gene-related peptide (CGRP). Human CGRP (hCGRP), rat CGRP (rCGRP), and the hCGRP analog [hCGRP-(8-37)] competed for the binding of [125I]hCGRP, whereas salmon calcitonin (sCT) and CGRP-(22-37) were very weak in displacing [125I]hCGRP binding. In accordance with these binding data, CGRP stimulated adenylate cyclase activity in these membrane preparations in a concentration-dependent manner, with an EC50 similar to that of the Kd for binding. In the same preparations, sCT was ineffective in stimulating adenylate cyclase activity, suggesting that porcine kidney medullary membranes possess receptors specific for CGRP. Further hCGRP-(8-37), a CGRP antagonist, inhibited CGRP-stimulated adenylate cyclase activity in a competitive manner. Covalent cross-linking of [125I]hCGRP to these membranes resulted in the specific labeling of one major band at approximately 30,000 mol wt and two minor bands at about 58,000 and 78,000 mol wt. The presence of CGRP receptors and their coupling to adenylate cyclase suggest a role for CGRP in kidney function, such as local regulation of the microcirculation, electrolyte transport, or water homeostasis in the porcine kidney.
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PMID:Identification and characterization of calcitonin gene-related peptide receptors in porcine renal medullary membranes. 164 52

Specific receptors for calcitonin gene-related peptide (CGRP) were identified and characterized on plasma membranes from the interleukin-1 secreting murine macrophage-like cells line P388 D1. The binding of [125I]-rat CGRP I was time-dependent, reversible and the rate of dissociation of [125I]-rat CGRP I increased in the presence of GTP. Scatchard analysis was consistent with a single class of binding sites, with an apparent dissociation constant of 1.76 nM and a maximal binding capacity of 85.48 fmol/mg protein. In competitive displacement studies, rat CGRP I, human CGRP I and human CGRP II were equipotent to inhibit the binding of [125I]-rat CGRP I (IC50 = 4 nM) while rat CGRP II and the synthetic analogue [tyr(o)]-human CGRP I were ten-fold less potent. Porcine calcitonin and VIP did not inhibit tracer binding. In the presence of GTP, CGRP stimulation of adenylate cyclase was dose-dependent and strongly correlated with receptor occupation. These results indicate that the P388 D1 macrophage-like cell line expresses CGRP specific receptors functionally coupled to adenylate cyclase, which may be involved in CGRP-mediated macrophage immune response.
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PMID:Characterization of calcitonin gene-related peptide receptors and adenylate cyclase response in the murine macrophage cell line P388 D1. 165 11

Interleukin 6 (IL-6) production was shown to be stimulated by vasoactive intestinal peptide via cAMP dependent signal transduction pathway in the pituitary. We were interested in whether other hypothalamic neuropeptides, which activate adenylate cyclase in the pituitary, also stimulate pituitary IL-6 production. Whereas vasoactive intestinal peptide was effective in stimulating pituitary IL-6 production only at concentrations of 10(-6) M or higher, pituitary adenylate cyclase activating polypeptide with 38 residues (PACAP38) and calcitonin gene-related peptide (CGRP) at concentrations from 10(-10) to 10(-9) M significantly stimulated IL-6 production. Similar effective concentrations of each peptide were required for activating adenylate cyclase, as measured by extracellular cAMP accumulation. H89, a specific inhibitor of cAMP dependent protein kinase (protein kinase A), inhibited IL-6 production stimulated by PACAP38, CGRP, and (Bu)2cAMP. However, H89 failed to inhibit the IL-6 production stimulated by lipopolysaccharide, a ligand which enhanced IL-6 production in the absence of cAMP accumulation. Two other peptides which are known to activate pituitary adenylate cyclase, corticotropin-releasing factor and GRF failed to stimulate IL-6 production in pituitary cells. Using discontinuous Percoll gradients to fractionate the pituitary cells, the greatest PACAP38-stimulated IL-6 secretion was observed in the low density fraction 1 (F1). This fraction also contained the highest percentage of folliculo-stellate (FS) cells, one of the nonhormone secreting pituitary cells. However, the largest PACAP38-induced accumulation of cAMP was observed in F4. These results suggest that the production of IL-6 stimulated by PACAP and CGRP is mediated by the adenylate cyclase/protein kinase A signal transduction system. FS cells appear to be the most likely target cell type for PACAP-induced IL-6 production. However, IL-6 producing FS cells may not be an exclusive target for PACAP in the pituitary.
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PMID:Neuropeptide regulation of interleukin-6 production from the pituitary: stimulation by pituitary adenylate cyclase activating polypeptide and calcitonin gene-related peptide. 165 84

When T47D cells were maintained long term in medium containing 0.1 mumol cortisol/l, calcitonin receptor (CTR) expression was stimulated compared with the very low levels of binding in untreated cells grown from frozen stocks. The time-course of the appearance of CTR following treatment with cortisol was slow, requiring up to 3 weeks of continuous exposure of the cells to the steroid. Binding capacity of control cells also increased slowly with time in culture, but after 3 months was only 20-30% of that in cells continuously treated with cortisol. Removal of cortisol resulted in rapid loss of CTR so that binding was reduced to approximately 50% of treated cell levels within 1 week of removal. Scatchard analysis of the binding data showed that the increased binding capacity induced by cortisol was due solely to a change in average receptor number per cell, with no change in receptor affinity. That this induction of CTR was due to a glucocorticoid effect was shown by the more rapid (less than 96 h) and more potent (less than 1 nmol/l) action of dexamethasone than of cortisol. In addition, induction was inhibited by the glucocorticoid inhibitor RU486. The induced receptors were shown to be functional, since salmon calcitonin-stimulated adenylate cyclase was induced in parallel with CTR. These results indicate that glucocorticoids are potential regulators of the CTR.
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PMID:Induction of calcitonin receptor expression by glucocorticoids in T47D human breast cancer cells. 165 43

We examined the effects of calcitonin gene-related peptide (CGRP) on the membrane currents of single atrial and ventricular cells of guinea pig heart. The tight-seal whole-cell voltage-clamp technique was used. In atrial cells, like isoproterenol, CGRP increased the L-type Ca channel current (ICa.L) in a concentration-dependent manner. Human CGRP-(8-37), a putative CGRP receptor antagonist, completely abolished the CGRP-induced increase of ICa.L. Although the effects of CGRP were similar to those of isoproterenol, propranolol, a beta-adrenergic receptor antagonist, did not affect the CGRP-induced increase of ICa.L. After ICa.L had been maximally activated by isoproterenol (2 microM) or intracellular cyclic adenosine 5'-monophosphate (100 microM), CGRP failed to increase ICa.L. Acetylcholine antagonized the effects of CGRP on ICa.L. Unlike the effects on atrial cells, CGRP had no significant effects on the membrane currents of ventricular myocytes. These results indicate that CGRP increases ICa.L via adenylate cyclase activation by binding to specific membrane receptors in cardiac atrial myocytes. Furthermore, CGRP receptors are expressed in atrial cells but probably not in ventricular cells.
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PMID:Effects of calcitonin gene-related peptide on membrane currents in mammalian cardiac myocytes. 166 40

It is uncertain whether adenosine 3',5'-cyclic monophosphate (cAMP) or the inositol-calcium pathway mediates the stimulation of bone resorption by parathyroid hormone (PTH). Incubation of bone organ cultures with cAMP analogues and forskolin has not resolved this question because of the cellular inhomogeneity of bone and the consequent presence of adenylate cyclase-linked receptors for both PTH and calcitonin, hormones with opposite effects on bone resorption. We have used two new inhibitors of adenylate cyclase, 9-(tetrahydro-2-furyl)adenine (SQ 22536) and 2',5'-dideoxyadenosine (DDA), to directly reassess the role of cAMP in PTH-stimulated osteolysis. SQ 22536 (0.01-1.0 mM) and DDA (0.01-1.0 mM) completely blocked PTH stimulation of cAMP production measured in the absence of a phosphodiesterase blocker. In the presence of 1 mM 3-isobutyl-1-methylxanthine, half-maximal inhibition of PTH-induced cAMP production occurred with 0.2 mM SQ and 0.1 mM DDA, respectively. These concentrations of SQ and DDA had no effect on PTH-stimulated 45Ca release from calvaria, although both agents inhibited bone resorption when present at concentrations of 1-2 mM. At these levels, SQ and DDA caused equivalent inhibition of 45Ca release stimulated by 1,25-dihydroxyvitamin D3 but did not affect basal 45Ca release or [3H]-phenylalanine incorporation. It is concluded that substantial blockade of PTH-induced cAMP production does not affect this hormone's stimulation of bone resorption, which is therefore likely to be mediated by another intracellular messenger system, possibly calcium. In millimolar concentrations, SQ and DDA appear to be nonspecific blockers of osteoclastic bone resorption.
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PMID:Adenylate cyclase blockers dissociate PTH-stimulated bone resorption from cAMP production. 169 85

Distal nephron segments are heterogenous with respect to adenylate cyclase responses to stimulation with parathyroid hormone (PTH) or calcitonin (CT). We examined effects of these hormones and of 8-(p-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (CPTcAMP) on net Ca absorption (Jnet Ca2+, pmol.min-1.mm-1) in rabbit distal nephron segments by in vitro microperfusion technique. We studied three segments, including distal convoluted tubule (DCT), connecting tubule (CNT), and cortical collecting duct (CCD). PTH (1 nM) in bath significantly increased Jnet Ca2+ from 2.28 +/- 0.35 to 9.44 +/- 1.13 in CNT, but did not affect Jnet Ca2+ in DCT or CCD. CT (1 nM) in bath significantly increased Jnet Ca2+ from 1.58 +/- 0.29 to 4.45 +/- 1.01 in DCT, whereas it did not affect Jnet Ca2+ either in CNT or in CCD. CPTcAMP (30 microM) in bath significantly increased Jnet Ca2+ from 2.29 +/- 0.42 to 3.97 +/- 0.43 in DCT and from 2.43 +/- 0.18 to 5.83 +/- 0.37 in CNT, but it did not affect Jnet Ca2+ in CCD. When Na+ was removed from bathing fluid or when 0.1 mM ouabain was added to bath, Jnet Ca2+ in both DCT and CNT significantly decreased. Furthermore, stimulatory effects of PTH and CT on Ca2+ absorption in the respective segments were abolished under these conditions. These results suggest that PTH and CT increase Ca2+ absorption in CNT and DCT, respectively, through cAMP-mediated mechanisms. Presence of a basolateral Na(+)-Ca2+ exchange process seems to be a prerequisite for effects of these hormones. However, exact intracellular mechanisms remain uncertain.
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PMID:Effects of PTH, calcitonin, and cAMP on calcium transport in rabbit distal nephron segments. 169 36

In the porcine renal epithelial cell line, LLC-PK1, activation of the cAMP-dependent signal transduction pathway induces the urokinase-type plasminogen activator (uPA) gene. We show here that the cAMP response is enhanced when the intracellular calcium concentration is increased. When LLC-PK1 cells were treated with the calcium ionophore ionomycin alone, there was no uPA mRNA accumulation. However, in the presence of ionomycin the dose-response of 8-bromo-cAMP (Br-cAMP) with respect to uPA mRNA accumulation was shifted toward the lower concentrations of Br-cAMP. A Northern blot analysis after the inhibition of RNA synthesis and nuclear run-on assays showed that the synergistic effect of Ca2+ could be attributed to increases in uPA gene transcription and mRNA stability. In the presence of cycloheximide, a protein synthesis inhibitor, uPA mRNA was stabilized, but the effect of ionomycin on Br-cAMP-induced mRNA accumulation was still maintained. The result suggests that the Ca2+, at least on transcription, does not require new protein synthesis. Ionomycin treatment did not modify the activity of the cAMP-dependent protein kinase, suggesting that Ca2+ either affects a step in the pathway between the kinase and the uPA gene, or acts independently of the cAMP-dependent protein kinase pathway. The effect of ionomycin was not suppressed by protein kinase C down-regulation nor by inhibitors of calmodulin. Synergism was also observed when Br-cAMP was replaced with calcitonin, a peptide hormone which is coupled to adenylate cyclase, and when ionomycin was replaced with another ionophore A23187, suggesting that the synergism is due to an interaction between cAMP-dependent and Ca2(+)-dependent signal transduction pathways.
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PMID:Ca2+ potentiates cAMP-dependent expression of urokinase-type plasminogen activator gene through a calmodulin- and protein kinase C-independent mechanism. 170 Nov 76


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