Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PTH sensitive adenylate cyclase activity was measured in 9 different segments of the nephron, isolated by microdissection from collagenase-treated rabbit kidney slices. The enzyme of the following segments was stimulated by PTH, 1 U/ml: PCT. (proximal convoluted tubule); PR (pars recta); CAL (cortical portion of the thick ascending limb); DCT (distal convoluted tubule); BCT (first, branched portion of the collecting tubule); the segments which did not respond to PTH were: TDL (thin descending limb): MAL (medullary portion of the thick ascending limb); CCT (cortical portion of the collecting tubule distally adjacent to BCT); MCT (collecting tubule from the outer medulla). PTH sensitive adenylate cyclase per mm tubule in PR was half that measured in PCT. Half maximal stimulation corresponded to 50-100mm U/ml PTH (1-2 times 10-8M) in both PCT and PR, and to about 350 mm U/ml in CAL. PTH (1 U/ml) stimulation factors ranged from 5 to 60 depending on the structures. It is concluded that in addition to PCT and PR, CAL and BCT might be target structures involved in the physiological actions of PTH on the kidney.
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PMID:PTH sensitive adenyl cyclase activity in different segments of the rabbit nephron. 16 68

Atrial natriuretic factor (ANF) has been suggested to exert a tubular effect on the mammalian nephron, perhaps in part by interacting with other hormones. In the present study, the effect of ANF was examined on glomeruli (Gm) and different renal tubule segments including medullary (MAL) and cortical thick ascending limb (CAL) and cortical (CCT), outer medullary (OMCT) and inner medullary collecting tubules (IMCT). This effect of ANF was assessed by alteration in adenylate cyclase and cGMP in the various nephron segments in the presence and absence of arginine vasopressin (AVP), parathyroid hormone (PTH) and calcitonin (SCT). An effect of ANF (10(-8) M) was not demonstrated on adenylate cyclase (fmol cAMP formed/30 min/micrograms protein) in Gm, CAL, MAL, CCT, OMCT or IMCT. Nor did ANF (10(-8) M) interfere with the effect of PTH (5 IU/ml) on the Gm (PTH 35.1 +/- 3.7 vs. PTH + ANF 32.5 +/- 1.8, NS), CAL (PTH 50.5 +/- 10.9 vs. PTH + ANF 46.2 +/- 1.4, NS) or AVP (10(-8) M) on the CCT (AVP 40.8 +/- 6.6 vs. AVP + ANF 33.0 +/- 3.1, NS), OMCT (AVP 56.0 +/- 11.8 vs. AVP + ANF 42.1 +/- 6.7, NS), IMCT (AVP 66.5 +/- 4.6 vs. AVP + ANF 53.5 +/- 7.0, NS) or MAL (AVP 15.5 +/- 1.6 vs. AVP + ANF 14.0 +/- 2.6, NS). ANF also did not affect SCT (1.5 x 10(-8) M)-induced adenylate cyclase on CCT (SCT 69.8 +/- 11.3 vs. SCT + ANF 79.9 +/- 7.2, NS). ANF (10(-8) M), however, significantly increased cGMP in the Gm (6.4 +/- 1.7 to 121.3 +/- 32.4 fmol/micrograms protein, P less than 0.001) and IMCT (0.63 +/- 0.16 to 1.46 +/- 0.29 fmol/micrograms protein, P less than 0.05). However, no effect of ANF on cGMP was observed in the CAL, CCT, OMCT, and MAL even at 10(-7) M ANF. PTH (5 IU/ml) did not alter either basal or ANF-stimulated cGMP in the Gm. Also, specific ANF binding was studied in the microdissected IMCT. Kd was 6.08 x 10(-9) M and Bmax was 8.07 x 10(-11) M.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enzymatic and binding effects of atrial natriuretic factor in glomeruli and nephrons. 254 Mar 77

The major tubular effects of [8-Arg]vasopressin (AVP) in regulation of renal water excretion are initiated by stimulation of adenylate cyclase (AdC) coupled with V2 receptors. We explored whether the AVP-sensitive AdC is present in both collecting tubules and the thick ascending limb of Henle's loop of human and canine kidney. In cortical collecting tubule (CCT) and medullary collecting tubules (MCT) of human kidney, AdC was markedly stimulated by AVP [maximum change from basal level (delta), +2700%] and the the nonhormonal stimulatory agent forskolin (delta, +2000%). In human CCT, the effects of both compounds were synergistic. In contrast, AVP had no effect on AdC in either the medullary (MAL) or cortical (CAL) segment of the thick ascending limb of Henle's loop of human kidney; AVP also did not stimulate AdC in CAL or MAL in the presence of forskolin. Similar to that in the human kidney, in the canine kidney, AdC in CCT and MCT was markedly stimulated by AVP and forskolin (delta, +1000%), but AVP had no effect on AdC in CAL and MAL of the canine kidney. In intact tubules dissected from dog kidney and incubated in vitro, AVP markedly increased cAMP accumulation in MCT. AVP also elicited a small but detectable increase in cAMP accumulation in MAL. From these observations, we conclude that AVP-sensitive AdC is well developed in collecting tubules, but that AVP-sensitive AdC is absent in MAL and CAL of human kidney. Likewise, in canine nephron, the AVP-sensitive AdC of MAL and CAL is rudimentary or very labile. These findings suggest that the unresponsiveness of the AdC-cAMP system to AVP in segments of the thick ascending limb of Henle's loop may be a factor that accounts for a relatively low maximum osmotic concentration of urine which can be achieved by human or canine kidneys.
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PMID:The vasopressin-sensitive adenylate cyclase in collecting tubules and in thick ascending limb of Henle's loop of human and canine kidney. 298 37

A polyuric syndrome with nephrogenic diabetes insipidus (NDI) is a frequent consequence of prolonged administration of lithium (Li) salts. Studies in the past, mainly the acute and in vitro experiments, indicated that Li ions can inhibit hydroosmotic effect of [8-arginine]vasopressin (AVP) at the step of cAMP generation in vitro. However, the pathogenesis of the NDI due to chronic oral administration of low therapeutic doses of Li salts is not yet clarified. We conducted a comprehensive study to clarify the mechanism by which Li administered orally for several weeks induces polyuria and NDI in rats. Albino rats consuming a diet which contained Li (60 mmol/kg) for 4 wk developed marked polyuria and polydipsia; at the end of 4 wk the plasma Li was 0.7 +/- 0.09 mM (mean +/- SEM; n = 36). Li-treated rats had a significantly decreased (-33%) tissue osmolality in papilla and greatly reduced cortico-papillary gradient of urea (cortex--43%; medulla--64%; papilla--74%). Plasma urea was significantly (P less than 0.001) lower in Li-treated rats (5.4 +/- 0.2 mM) compared with controls (6.8 +/- 0.3 mM). Medullary collecting tubules (MCT) and papillary collecting ducts (PCD) microdissected from Li-treated animals had higher content of protein than MCT and PCD from the control rats. The cAMP accumulation in response to AVP added in vitro was significantly (delta = -60%) reduced. Also, the cAMP accumulation in MCT and PCD after incubation with forskolin was markedly lower in Li-treated rats. Addition of 0.5 mM 1-methyl,3-isobutyl-xanthine did not restore the cAMP accumulation in response to AVP and forskolin in MCT from Li-treated animals. In collecting tubule segments from polyuric rats with hypothalamic diabetes insipidus (Brattleboro homozygotes) the AVP-dependent cAMP accumulation was not diminished. The activity of adenylate cyclase (AdC) in MCT of Li-treated rats, both the basal and the activity stimulated by AVP, forskolin, or fluoride, was significantly (delta approximately equal to -30%) reduced, while the activity of cAMP phosphodiesterase (cAMP-PDIE) in the same segment showed no significant difference from the controls. Also, the content of ATP in MCT microdissected from Li-treated rats and incubated in vitro did not differ from controls. The rate of [14C]succinate oxidation to 14CO2 in MAL was inhibited (-77%) by 1 mM furosemide, which indicates that this metabolic process is coupled with NaCl cotransport in MAL. The rate of (14)CO(2) production from [14C]succinate in MAL was not significantly different between control and Li-treated rats. In MCT of control rats, the rate of [14C]succinate oxidation was approximately 3 times lower than in MAL. The rate of (14)CO(2) production from [(14)C]succinate in MCT of Li-treated rats was significantly (delta +33%) higher than in MCT dissected from control rats. Based on these results, we conclude that at least two factors play an important role in the pathogenesis of NDI consequent to chronic oral administration of Li: (a) decreased ability of MCT and PCD to generate and accumulate cAMP in response to stimulation by AVP; this defect is primarily due to diminished activity of AdC in these tubular segments caused by prolonged exposure to Li; and (b) lower osmolality of renal papillary tissue, due to primarily to depletion of urea, which decreases osmotic driving force for water reabsorption in collecting tubules. On the other hand, NaCI reabsorption in MAL is apparently not affected by chronic Li treatment.
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PMID:Pathogenesis of nephrogenic diabetes insipidus due to chronic administration of lithium in rats. 298 35

Rabbit nephron segments of proximal convoluted tubules (PCT); proximal straight tubules (PST); cortical and medullary thick ascending limbs of Henle's loop (CAL, MAL); and cortical, outer medullary, and inner medullary collecting tubules (CCT, OMCT, IMCT) were individually microdissected and grown in monolayer culture in hormone supplemented, defined media. Factors favoring a rapid onset of proliferation included young donor age, distal tubule origin, and the addition of 3% fetal calf serum to the medium. All primary cultures had polarized morphology with apical microvilli facing the medium and basement membrane-like material adjacent to the dish. Differentiated properties characteristic of the tubular epithelium of origin retained in cultures included ultrastructural characteristics and cytochemically demonstrable marker enzyme proportions. PCT and PST were rich in alkaline phosphatase; CAL stained strongly for NaK-ATPase; CCT contained two cell populations with regard to cytochrome oxidase reaction. A CCT-specific anti-keratin antibody (aLEA) was immunolocalized in CCT cultures, and a PST cytokeratin antibody stained PST cultures. The biochemical response of adenylate cyclase to putative stimulating agents was the same in primary cultures as in freshly isolated tubules. In PCT and PST adenylate cyclase activity was stimulated by parathyroid hormone (PTH) but not by arginine vasopressin (AVP); CAL and MAL adenylate cyclase was stimulated by neither PTH nor AVP; CCT, OMCT, and IMCT adenylate cyclase was stimulated by AVP but not by PTH. NaF stimulated adenylate cyclase activity in every cultured segment. It is concluded that primary cultures of individually microdissected rabbit PCT, PST, CAL, MAL, CCT, OMCT, and IMCT retain differentiated characteristics with regard to ultrastructure, marker enzymes, cytoskeletal proteins, and hormone response of adenylate cyclase and provide a new system for studying normal and abnormal functions of the heterogeneous tubular epithelia in the kidney.
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PMID:Retention of differentiated characteristics by cultures of defined rabbit kidney epithelia. 381 2

Interactions between AVP and prostaglandins were investigated in MAL and MCT microdissected from the rat outer medulla. Incubation of MCT with 14C-arachidonic acid resulted in the formation of 14C-PGE2 and 14C-PGF2 alpha; however, when MAL was incubated under the same conditions, only traces of prostaglandins were formed. Prostaglandin synthesis in MCT was inhibited (-50%) by the prostaglandin cyclo-oxygenase inhibitor ibuprofen (10(-6)M). Preincubation with ibuprofen enhanced the stimulation of adenylate cyclase by 5 x 10(-9)M AVP in MCT but, in contrast, decreased the stimulation of adenylate cyclase by AVP in MAL. The effects of a second PG cyclo-oxygenase inhibitor naproxen (10(-5)M) were similar to those of ibuprofen. Ibuprofen did not influence cAMP phosphodiesterase activity in MCT or in MAL. Exogenous PGE2 or PGF2 alpha (10(-6)M) had no effect on either basal or AVP-stimulated adenylate cyclase activity in MCT. The present results demonstrated that MCT but not MAL is a site of active synthesis and accumulation of prostaglandin. Although both MAL and MCT have AVP-sensitive adenylate cyclase, incubation with prostaglandin cyclo-oxygenase inhibitors have, in the presence of arachidonic acid, an opposite effect on this enzyme in these two segments, resulting in increased AVP stimulation in MCT and decreased stimulation in MAL. Results also suggest that products of prostaglandin synthesis from arachidonic acid inhibit AVP-sensitive adenylate cyclase activity in MCT but not that located in MAL. Although not totally excluding the primary prostaglandins (PGE2, PGF2 alpha), these observations suggest that they are not responsible for AVP modulation in MCT.
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PMID:Vasopressin-prostaglandin interactions in isolated tubules from rat outer medulla. 624 5

The effects of PDN on VP-sensitive cAMP metabolism were examined in MCT and MAL microdissected from the rat kidney. VP-sensitive adenylate cyclase activity was significantly reduced (delta -46%; p less than 0.05) in MAL of PDN rats but, in sharp contrast, was significantly increased (delta +79%; p less than 0.02) in MCT of PDN rats compared to controls. cAMP phosphodiesterase activity was significantly increased in both MAL (delta +59%; p less than 0.005) and MCT (delta +79%; p less than 0.001) of PDN rats compared to controls. The increase in cAMP accumulation in MAL measured in response to VP in intact tubules did not differ between PDN and controls, whereas cAMP accumulation in response to VP was significantly higher (delta +127%; p less than 0.001) in MCT of PDN rats compared to controls. The present results would indicate that the observed in vivo resistance to the antidiuretic effect of VP that occurs in PDN is not due to an impairment in VP-sensitive cAMP accumulation in MCT, but would rather suggest that a defect exists at a cellular step subsequent to cAMP generation. In addition, our results illustrate that the extent and directionality of in situ accumulation of cAMP measured in intact tubules cannot always be predicted from rhe activities of enzymes controlling its synthesis and degradation (adenylate cyclase and cAMP phosphodiesterase), which are measured in vitro in disrupted tubules.
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PMID:Effect of potassium depletion on the vasopressin-sensitive cyclic AMP system in rat outer medullary tubules. 627 83

Steroid hormonal activation of the Na+-K+-ATPase enzyme was examined in enriched preparations of outer medullary collecting tubules (MCT) and outer medullary thick ascending limbs of the loop of Henle (MAL), prepared by sedimentation through a discontinuous Ficoll gradient. Using morphological criteria, there was a 2.9-fold enrichment of MCT in fraction 1 when compared with fraction 2 and a 2.2-fold enrichment of MAL in fraction 2 when compared with fraction 1. This separation was further defined using biochemical markers. Na+-K+-ATPase activity, Mg2+-ATPase activity, and the adenylate cyclase response to a number of hormones each supported the morphologic definition of separation. The two preparations were challenged in vitro with both aldosterone and dexamethasone. In fraction 1, the fraction enriched in the MCT, 10(-8) M aldosterone stimulated Na+-K+-ATPase activity by 37%. The same concentration of dexamethasone was without effect. In contrast, 10(-8) M dexamethasone stimulated Na+-K+-ATPase activity by 27% in fraction 2, the fraction enriched in the MAL. In this fraction an equimolar concentration of aldosterone was without effect. Thus, the regulation of Na+-K+-ATPase activity by mineralocorticoids on the one hand and by glucocorticoids on the other would appear to be discontinuously localized along the length of the outer medullary distal nephron.
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PMID:Steroid regulation of Na+-K+-ATPase: differential sensitivities along the nephron. 632 15

Saccharomyces cerevisiae CEN.PK 113-7D is widely used for metabolic engineering and systems biology research in industry and academia. We sequenced, assembled, annotated and analyzed its genome. Single-nucleotide variations (SNV), insertions/deletions (indels) and differences in genome organization compared to the reference strain S. cerevisiae S288C were analyzed. In addition to a few large deletions and duplications, nearly 3000 indels were identified in the CEN.PK113-7D genome relative to S288C. These differences were overrepresented in genes whose functions are related to transcriptional regulation and chromatin remodelling. Some of these variations were caused by unstable tandem repeats, suggesting an innate evolvability of the corresponding genes. Besides a previously characterized mutation in adenylate cyclase, the CEN.PK113-7D genome sequence revealed a significant enrichment of non-synonymous mutations in genes encoding for components of the cAMP signalling pathway. Some phenotypic characteristics of the CEN.PK113-7D strains were explained by the presence of additional specific metabolic genes relative to S288C. In particular, the presence of the BIO1 and BIO6 genes correlated with a biotin prototrophy of CEN.PK113-7D. Furthermore, the copy number, chromosomal location and sequences of the MAL loci were resolved. The assembled sequence reveals that CEN.PK113-7D has a mosaic genome that combines characteristics of laboratory strains and wild-industrial strains.
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PMID:De novo sequencing, assembly and analysis of the genome of the laboratory strain Saccharomyces cerevisiae CEN.PK113-7D, a model for modern industrial biotechnology. 2244 15