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)

The present study was designed to examine the extent to which calcium modulates vasopressin (AVP)-stimulated cyclic AMP (cAMP) accumulation in microdissected rat papillary collecting ducts (PCD), and to identify the mechanism(s) involved. Using a submaximal concentration of vasopressin (1 nM), ionophore A23187-mediated increases in intracellular calcium inhibited AVP-dependent cAMP levels by 69% (P less than 0.001) in the absence of the cAMP-phosphodiesterase inhibitor 1-methyl-3-isobutyl xanthine (MIX). The degree of inhibition was significantly reduced (-47%; P less than 0.01) in the presence of MIX. Compared to controls (1.2 mM calcium), AVP-sensitive cAMP accumulation was significantly reduced (-34%; P less than 0.05) when PCD were incubated in a medium containing an increased (5.0 mM) calcium concentration. In the presence of MIX 5.0 mM calcium had no effect on cAMP levels. Conversely, compared to controls, a calcium-free medium increased AVP-dependent cAMP accumulation by 89% (P less than 0.01) in the absence of MIX, and similarly by 82% (P less than 0.05) in the presence of MIX. These data demonstrate that calcium can modulate AVP-dependent cAMP accumulation in PCD as a result of effects on both adenylate cyclase and cAMP phosphodiesterase activities.
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PMID:Modulation of vasopressin-sensitive cyclic AMP levels by calcium in papillary collecting tubules. 284 Nov 78

Vasopressin (AVP) plays a key role in maximal urine concentration by stimulating NaCl reabsorption in the medullary thick ascending limbs of Henle (MTAL) and by increasing water permeability in the medullary collecting tubules (MCT). These effects of AVP in MTAL and MCT are mediated by activation of adenylate cyclase. Because effects of high ambient Ca2+ on AVP-sensitive adenosine 3',5'-cyclic monophosphate (cAMP) production are quite different in MTAL and MCT, we examined whether the Ca2+-calmodulin system is involved differently in AVP-sensitive cAMP production in MTAL and MCT of mouse kidney using two dissimilar calmodulin inhibitors, trifluoperazine (TFP) and W-7. TFP and W-7 inhibited AVP-sensitive cAMP production in both nephron segments in a dose-dependent manner with maximal inhibition of both agents being greater than 90%. A half-maximal inhibition by TFP and W-7 was about 45, 100 microM in MTAL and about 40, 40 microM in MCT, respectively. The inhibitory effect of W-5, a chemically similar to W-7 but less potent calmodulin inhibitor, was significantly less than that of W-7 in both nephron segments. TFP and W-7 but not W-5 also inhibited glucagon-sensitive cAMP production in MTAL. W-7 inhibited forskolin-sensitive cAMP production but the inhibition by W-5 was significantly less than that by W-7 in MTAL and MCT. Results suggest that AVP-sensitive cAMP production is MCT.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:AVP-sensitive cAMP production is dependent on calmodulin in both MTAL and MCT. 284 48

Previous studies have established the presence of parathyroid hormone (PTH)-sensitive adenylate cyclase activity in cultured human skin fibroblasts. The present study was undertaken to identify and quantitate PTH receptors directly in such cells. Human dermal fibroblast cell line CRL 1564 was found to possess specific binding sites for [125I]PTH(1-34). These sites bound PTH selectively; bovine and human PTH(1-34) and PTH(1-84) competed for [125I]PTH(1-34) binding sites, whereas the unrelated peptides calcitonin, insulin, AVP, angiotensin II, and ACTH(1-24) were inactive even at micromolar concentrations. Competitive binding experiments demonstrated the presence of binding site heterogeneity. These data fit a "two-site" model (p less than 0.001) in which one binding component has high affinity (Kd = 2.5 ng/ml = 0.6 nM) and low capacity (10(4) sites/cell) while the other has low affinity (Kd = 5.9 micrograms/ml = 1.5 microM) and high capacity (greater than 10(7) sites/cell). Similar high- and low-affinity [125I]bPTH(1-34) binding sites were seen also in CRL 1564 membranes containing a PTH-responsive adenylate cyclase. The Kd of the high-affinity sites was identical to the concentration of unlabeled bPTH(1-34) (4.2 ng/ml = 1.0 nM) required to half-maximally elevated cyclic AMP in CRL 1564 cells. Affinity labeling of specific PTH binding sites revealed the presence of multiple components with Mrs of 85, 70, 40, 33, and 23 kD on SDS-PAGE. Competition experiments did not disclose structurally discrete high- and low-affinity sites. Thus, structurally homologous PTH receptors in human skin fibroblasts apparently can assume two affinity states: (i) a high-affinity state coupled to adenylate cyclase and (ii) a low-affinity state that may represent uncoupled receptors.
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PMID:Parathyroid hormone receptors in human dermal fibroblasts: structural and functional characterization. 285 22

The effect of synthetic rat atrial natriuretic factor (ANF, Arg 101-Tyr 126) was evaluated in an in-vitro model of rat hypothalamo-neurohypophysial complex (HNC) in organ culture in which part of hypothalamus containing a portion of undamaged magnocellular neurons is separated from posterior pituitary by a fluid tight barrier with an intact stalk connecting both structures. ANF, when added to the medium at the hypothalamus site at concentrations of 3 X 10(-5) M to 3 X 10(-7) M, did not change basal AVP release from the posterior pituitary. Similarly, a shorter form of ANF (Cys 105-Tyr 126), reported to be highly potent in inhibiting adenylate cyclase activity in various tissues, exerted no effect on AVP excretion from HNC in organ culture. The application of an hyperosomotic medium (osmolality 324 +/- 2 mOsm/kg H2O) to the hypothalamic side, together with ANF (3 X 10(-6) M), significantly lowered osmotically-stimulated AVP release. It is concluded that ANF has no effect on basal AVP release from HNC in culture and suppresses osmotically-stimulated AVP secretion in this in vitro model.
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PMID:Effect of synthetic atrial natriuretic factor on arginine vasopressin release by the rat hypothalamo-neurohypophysial complex in organ culture. 293 43

Neurohypophysial hormones stimulate the motility of tunica albuginea, epididymis, and vas deferens acting through oxytocin (OT) and V1 vasopressin receptors. To test the hypothesis that these hormones are involved also in the regulation of seminal vesicle physiology, we studied binding of [3H]OT and [3H] arginine vasopressin ([3H]AVP) to porcine seminal vesicle membranes. Neurohypophysial hormones bind to two different classes of sites. The first class shows low capacity (35 fmol per mg of protein) and a very high affinity (Kd less than 1 nM) for both the labeled ligands. The second class is characterized by a high capacity (2000 fmol per mg of protein) and a high affinity for AVP (Kd approximately equal to 2.5 nM), whereas OT has 160 times lower affinity. Lysine vasopressin and the V1 antagonist [1-deaminopenicillamine, 2-(O-methyl)tyrosine]Arg8-vasopressin compete with high affinity with [3H]AVP binding, whereas the V2 agonist [1-deamino,4-valine]D-Arg8-vasopressin (dVDAVP) is 110 times less potent than AVP. The OT agonist [Thr4,Gly7]OT and the OT antagonist [1(beta-mercapto-beta, beta-cyclopentamethylene propionic acid), 2-(O-ethyl)tyrosine, 8-ornithine]vasotocin failed to affect [3H]AVP binding. These findings seem to suggest that AVP interacts with the V1 vasopressin isoreceptor in porcine seminal vesicle membranes. However, AVP stimulates adenylate cyclase activity in a dose-dependent fashion with an EC50 of 14 nM, whereas OT or dVDAVP has no effect at 100 nM. Moreover, a well-characterized V1 vasopressin antagonist, [1-(beta-mercapto-beta, beta-cyclopentamethylene propionic acid),2-(O-methyl)tyrosine]Arg8-vasopressin [d(CH2)5Tyr(Me)AVP], competes with [3H]AVP binding with an IC50 of 0.17 microM. These pharmacological properties are distinct from the previously described V1 and V2 vasopressin receptors and indicate the presence of a new class of AVP receptors. Although this vasopressin isoreceptor shares some pharmacological characteristics with the V1 (pressor) isoreceptor, it has low affinity for the V1 antagonist d(CH2)5-Tyr(Me)AVP and is linked to the adenylate cyclase system. The extremely high density of AVP receptors in porcine seminal vesicles (2 pmol per mg of protein) is comparable to the density of V2 vasopressin receptors in porcine renal medulla, suggesting a physiological role for vasopressin in the seminal vesicle.
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PMID:Identification and characterization of a vasopressin isoreceptor in porcine seminal vesicles. 294 37

Our molecular modeling studies suggested that the conformational effects of the "cystine-line" residue Pmp1-Cys6 on the cyclohexapeptide ring of the vasopressin antagonist [Pmp1,D-Phe2,Val4]AVP might be mimicked by substitution of D-aminoadipic acid at position 6 and cyclization of its side-chain carboxyl to the alpha-amine of residue 2. The peptide was prepared with DL-aminoadipic acid, and following cyclization, the two diastereomeric peptides were separated and purified by preparative high-performance liquid chromatography. The structure of each was confirmed by amino acid analysis and fast atom bombardment mass spectrometry. The chirality of the aminoadipic acid residue of each peptide was determined by chiral gas chromatography. The circular dichroism spectrum of each peptide was run and compared with the appropriate agonist and antagonist peptide standards. These peptides demonstrated in vitro poor V2-receptor affinity and an inability to inhibit or stimulate vasopressin-induced adenylate cyclase formation, suggesting that they lack one or more key features of the agonist/antagonist pharmacophore.
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PMID:Design, synthesis, and biological activity of a peptide mimic of vasopressin. 296 43

The urinary bladder of the toad Bufo marinus has been used to examine the effect on sodium transport, measured by short-circuit current, of natural antidiuretic hormones and several synthetic peptide analogs. In mammals, these synthetic analogs show specificity for different receptors, designated V1 and V2 receptors, whose biological responses are mediated by phosphatidyl inositol breakdown products or adenylate cyclase activity, respectively. All analogs stimulated SCC, with relative potencies AVT greater than AVP greater than Phe2 OVT (V1 agonist) much greater than d(CH2)5Tyr(Me)AVP (V1 antagonist) = d(CH2)5[D-Ile2,Abu4]AVP (V2 antagonist). The V1 and V2 antagonists inhibited the SCC response to AVT and Phe2OVT, with similar inhibitory potencies. We conclude that the stimulation of sodium transport by antidiuretic hormones involves one hormone receptor which does not show the selectivity of mammalian antidiuretic hormone receptors, and may represent a more primitive type of receptor.
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PMID:Response of toad urinary bladder to vasopressin analogs possessing V1 or V2 specificity. 296 74

The medullary thick ascending limb (MAL), but not the medullary collecting tubule (MCT), has been shown to have an impaired adenylate cyclase (AC) responsiveness to ADH and a selective hypoplasia in Brattleboro diabetes insipidus (DI) rats. Since chronic ADH administration has been found to increase epithelium volume and basolateral membrane surface area in MAL but not in MCT, we investigated whether chronic ADH infusion would affect the hormone-sensitive AC and the Na-K-ATPase activity--two markers of the basolateral membrane--in single micro-dissected portions of thick ascending limb and collecting tubule in DI rats. Results indicate that 1. in MAL of ADH-treated rats, AC responses to in vitro AVP and glucagon and Na-K-ATPase activity increased to the same extent as did epithelium volume (60-80%); 2. changes in the other segments were independent of any morphological alteration. In the cortical thick ascending limb, AVP and glucagon-sensitive AC decreased by 30-40% whereas Na-K-ATPase activity did not change. In the collecting tubule, AC response to in vitro AVP was not altered by ADH-treatment but glucagon-sensitive AC dropped by 50% and Na-K-ATPase activity doubled, independently of any variation in plasma aldosterone and glucagon levels. These results show that, in the MAL, the ADH-induced variations in enzyme activity are a reflection of the enlargement of the basolateral membrane surface area. Further studies are needed to clarify the origin of enzymatic alterations in the other segments.
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PMID:Influence of chronic ADH treatment on adenylate cyclase and ATPase activity in distal nephron segments of diabetes insipidus Brattleboro rats. 299 94

An extracellular adenosine responsive site that stimulates adenylate cyclase activity has been identified in several tissues. There is limited information on the presence and physiologic significance of adenosine receptors in well-defined segments of the mammalian nephron. We therefore examined the effect of adenosine and selected analogues on basal hydraulic conductivity in rabbit cortical collecting tubules (CCT) perfused in vitro. Adenosine and analogues with an intact ribose moiety produced a significant, sustained increase in hydraulic conductivity. No increase in hydraulic conductivity was seen in either time control CCT's or CCT's exposed to an adenosine analogue with an altered ribose moiety. These experiments are compatible with the presence of a functional adenosine receptor which requires an intact ribose moiety and acts to increase hydraulic conductivity in the mammalian CCT. An intracellular adenosine responsive site, termed the "P site," which inhibits adenylate cyclase activity, has also been described in several tissues. We therefore examined the effect of a P site agonist on hydraulic conductivity responses to arginine vasopressin, forskolin and cAMP. P site stimulation with 2'5' dideoxyadenosine inhibited the effect of AVP and of forskolin but not of cAMP to increase hydraulic conductivity. These results are compatible with a functional P site in the rabbit CCT which acts at the catalytic subunit of adenylate cyclase to inhibit hydraulic conductivity. Together, these results demonstrate purinergic modulation of basal and arginine vasopressin-stimulated water flux in the mammalian collecting tubule.
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PMID:Purinergic regulation of basal and arginine vasopressin-stimulated hydraulic conductivity in rabbit cortical collecting tubule. 300 63

We showed previously that increasing Ca2+ concentration in the incubation medium suppressed cAMP production in response to vasopressin (AVP), glucagon or forskolin in the medullary thick ascending limb of Henle (MTAL) but not in medullary collecting tubules of mouse kidney. In the present study, we examined, using nephron segments dissected from mouse kidney, whether the inhibitory effect of high Ca2+ is specific to MTAL. Increasing Ca2+ in the incubation medium from 1 to 5 mM inhibited cAMP production in response to parathyroid hormone (PTH), calcitonin, AVP or glucagon in cortical thick ascending limbs of Henle (CTAL), but dit not inhibit cAMP production stimulated by PTH or calcitonin in proximal convoluted tubules and that by AVP in cortical collecting tubules. In CTAL, high ambient Ca2+ also inhibited cAMP production stimulated by forskolin. Thus, our present data show that high Ca2+ inhibits cAMP production specifically in thick ascending limbs of Henle but not in the other nephron segments. High ambients Ca2+ may inhibit adenylate cyclase at postreceptor site(s) one of which may be the catalytic unit of the enzyme in TAL.
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PMID:High Ca2+ inhibits peptide hormone-dependent cAMP production specifically in thick ascending limbs of Henle. 302 19


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