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 primary structure of frog pituitary adenylate cyclase-activating polypeptide (PACAP) has recently been determined and the results show that the sequence of PACAP has been highly conserved during evolution. In particular, the structure of the 1-27 fragment of PACAP is identical in frog and mammals. Using an antiserum raised against PACAP27, we have investigated the distribution of PACAP-containing neurons in the central nervous system of the frog Rana ridibunda by the immunofluorescence technique. The main populations of immunoreactive perikarya were located in the medial and ventral diencephalon, i.e., the preoptic nucleus, the ventral and dorsal infundibular nuclei, the nucleus posterocentralis thalami, and the ventral and ventrolateral areas of the thalamus. In the telencephalon, sparse cell bodies were found in the nucleus accumbens septi, the amygdala, the pallial commissure, and the bed nucleus of the pallial commissure. In the hindbrain, the torus semicircularis, the nucleus profundus and the nucleus anteroventralis tegmenti of the mesencephalon also contained populations of PACAP-immunoreactive perikarya. Beaded nerve fibers were observed throughout the brain. Occasionally they formed bundles, e.g., from the ventral infundibulum to the external vascular layer of the median eminence, from the central thalamus to the optic tectum, and rostrocaudally, from the nucleus accumbens septi to the nucleus entopeduncularis. Other areas, such as the interpeduncular nucleus, the nucleus isthmi and the roots of cranial nerves V and VIII in the medulla oblongata, were also densely innervated. The adenylate cyclase-stimulating activity of PACAP was tested by using a static incubation technique for hypothalamic slices.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Immunohistochemical distribution and biological activity of pituitary adenylate cyclase-activating polypeptide (PACAP) in the central nervous system of the frog Rana ridibunda. 133 Dec 6

The modulatory role of protein kinase C (PK-C)- and Gi-protein-mediated signal transduction systems was studied in the cyclic variation of follicle-stimulating hormone (FSH)-stimulated cAMP production of rat seminiferous tubules. FSH (Metrodin, Serono, 30 mg/l) stimulated cAMP production 10-fold (p less than 0.01) in a 3 h incubation of 5 mm segments of seminiferous tubules of stages II-VI of the epithelial cycle, but only 2-fold (p less than 0.01) in stages VII-VIII. The PK-C activator 12-O-tetradecanoylphorbol 13-acetate (TPA, 100 nmol/l) suppressed the FSH effect on cAMP output by 50-70% (p less than 0.01) in stages II-VI, but had no effect in stages VII-VIII. If the tubular segments were preincubated for 3 h in the presence of pertussis toxin (PT, 100 micrograms/l), the FSH-stimulated cAMP production of stages VII-VIII increased by 100-200% (p less than 0.01), and now they also became responsive to the TPA suppression. Conversely, no effect of PT was observed in stages II-VI. Cholera toxin (CT, 100 micrograms/l) and forskolin (Fk, 100 mumol/l) nearly similarly stimulated the cAMP production in both stages studied (about 10-fold, p less than 0.01), and TPA and PT potentiated the effects in a non-additive fashion. In conclusion, both Gi-protein and PK-C-mediated mechanisms modulate cAMP production of rat seminiferous tubules. A clear cyclic variation can only be demonstrated in FSH-stimulated cAMP production, but not if the Gs-protein or adenylate cyclase are directly stimulated.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protein kinase C and Gi-protein mediated modulation of cAMP production in different stages of the rat seminiferous epithelium. 216 36

The stage-specific influence of the secretions from rat seminiferous tubules on the LH-stimulated testosterone production by rat Leydig cells in vitro was studied. The spent media from incubated seminiferous tubules (SMST) from stages VII-VIII of the seminiferous epithelial cycle caused about 50% inhibition of the LH-dependent testosterone production by a crude preparation of rat interstitial cells. The SMST from other stages had no effect on testosterone production. Mixed tubules of unidentified stages gave an intermediate response. When SMST from ten different stages of the seminiferous wave were compared, the most pronounced inhibitory activity was found in stages VI and VIII-XI, while SMST from stages I, VII and XIII-XIV had no inhibitory effects on interstitial cell testosterone production. No stimulation was found in this system. Prolonged incubation of the interstitial cells with SMST from stages VIII-XI resulted in loss of inhibitory activity after 12 h of incubation. Maximum inhibitory activity was noted after 3 h of incubation. The inhibitory activity of the SMST from stages VIII-XI was retained after prolonged dialysis, and was unchanged after heating the medium at 60 degrees C for 1 h. The activity did not seem to be due to the presence of proteolytic enzymes, since it was not influenced by addition of protease inhibitors. SMST from stages VIII-XI had no effect on the metabolism of [3H]testosterone added to the interstitial cell preparations. No inhibitory effect was observed when Leydig cells were incubated with dibutyryl cAMP instead of LH, suggesting an early influence on the LH-receptor-adenylate cyclase chain of events.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stage-specific inhibition of interstitial cell testosterone secretion by rat seminiferous tubules in vitro. 400 58

Increased platelet reactivity has been suggested in the pathogenesis of both arteriosclerosis and diabetic microangiopathy. Therefore, platelet function and platelet enzyme activities were assessed in a large group of 357 diabetics (256 patients with IDDM, aged 16-49 and 101 patients with NIDDM, aged 50-78) and 163 matched controls, and related to photographically documented retinopathy (Rd) and to peripheral vascular disease (PVD) as well as to plasma levels of von Willebrand factor (VIII R:Ag) as an indicator of endothelial damage. Patients with IDDM had increased platelet aggregation (PA, expressed as microM ADP threshold concentration) before Rd was detectable in comparison to control subjects (P less than 0.01). PA was further increased in patients with advanced Rd (P less than 0.01), whereas 20 newly diagnosed diabetics with IDDM exhibited normal PA. Patients with minimal Rd did not differ from patients without Rd. Plasma beta-thromboglobulin (reflecting platelet consumption in vivo) was enhanced significantly in patients with Rd only (P less than 0.05), as was malondialdehyde (MDA) production of platelets (as a measure of platelet endoperoxide formation). Factor VIII-related antigen in plasma was already increased in patients without Rd (P less than 0.05), yet more so in patients with Rd (P less than 0.01). Prostacyclin-stimulated adenylate cyclase activity (ACA) of platelets (as an antiaggregatory enzyme system) was twice as high in diabetics with advanced Rd compared with patients without Rd and with controls (P less than 0.01). Significant correlations were found between PA and plasma F VIII R: Hg, MDA production, and ACA of platelets.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Platelet enzyme activities in diabetes mellitus in relation to endothelial damage. 608 25

Adenylylcyclase is a membrane bound enzyme that catalyzes the conversion of ATP to cyclic AMP. Studies on the regulation of adenylylcyclase have been hampered by the small amount of this enzyme in the cell as well as by the instability of the catalytic activity. Cloning of multiple adenylylcyclase isoforms (types I though VIII) has indicated the presence of a large enzyme family, which is further subdivided into several smaller groups. Members within the same group share similar biochemical properties. The multiplicity of adenylylcyclase is made through at least three distinct mechanisms. First, each isoform is encoded by a distinct gene. Second, multiple isoforms are generated through possible alternative splicing from the same gene. Third, there is a mechanism to generate a half-molecule of adenylylcyclase via alternative polyadenylation. Overexpression of a distinct isoform in insect cells followed by purification has enabled researchers to examine the role of each specific isoform in vitro. The results have suggested that each isoform is regulated through distinct mechanisms. For example, type I adenylylcyclase is inhibited in the presence of beta gamma-subunits, while type II is stimulated. Other isoforms such as types V and VI are not affected. On the other hand, Gi alpha may directly inhibit each adenylylcyclase isoform. Further characterization of adenylylcyclase would be feasible using those clones in the future.
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PMID:[Multiplicity of adenylylcyclase and regulation of G-protein]. 803 69

The role of position 10 in the beta-turn region of glucagon was investigated by substituting chiral constrained amino acids and other modifications in the N-terminal region. A series of glucagon analogues have been designed and synthesized by incorporating beta-methylphenylalanine isomers (2S,3S, 2S,3R, 2R,3R, and 2R,3S) at position 10 in order to explore the structural and topographical requirements of the glucagon receptor, and, in addition, utilizing previous studies which indicated that antagonism could be enhanced by modifications (des-His1, Glu9) and a bulky group at position 5. The structures of the new analogues are as follows: [des-His1,-Tyr5,Glu9]glucagon-NH2 (II), [des-His1,Tyr5,Glu9,Phe10]glucagon-NH2 (III), [des-His1,Tyr5,Glu9,-Ala10]glucagon-NH2 (IV), [des-His1,Tyr5,Glu9,(2S,3R)-beta-MePhe10]glucagon-NH2 (V), [des-His1,-Tyr5,Glu9,(2S,3S)-beta-MePhe10]glucagon-NH2 (VI), [des-His1,Tyr5,Glu9,D-Tyr10]glucagon-NH2 (VII), [des-His1,Tyr5,Glu9,D-Phe10]glucagon-NH2 (VIII), [des-His1,Tyr5,Glu9,D-Ala10]glucagon-NH2 (IX), [des-His1,Tyr5,Glu9,(2R,3R)-beta-MePhe10]glucagon-NH2 (X), and [des-His1,Tyr5,Glu9,(2R,3S)-beta-MePhe10]glucagon-NH2 (XI). These analogues led to dramatically different changes in in vitro binding affinities for glucagon receptors. Their receptor binding potencies IC50 values (nM) are 2.3 (II), 4.1 (III), 395.0 (IV), 10.0 (V), 170.0 (VI), 74.0 (VII), 34.5 (VIII), 510.0 (IX), 120.0 (X), and 180.0 (XI). Analogues II, III, V, VI, and XI were found to be weak partial agonists/partial antagonists with maximum stimulation between 5%-9%, while the other compounds (IV and VII-X) were antagonists unable to activate the adenylate cyclase system even at concentrations as high as 10(-5) M. In competition experiments, all of the analogues caused a right shift of the glucagon-stimulated adenylate cyclase dose-response curve. The pA2 values were 6.60 (II), 6.85 (III), 6.20 (IV), 6.20 (V), 6.10 (VI), 6.50 (VII), 6.20 (VIII), 5.85 (IX), 6.20 (X), and 6.00 (XI). Putative topographical requirements of the glucagon receptor for the aromatic side chain conformation in position 10 of glucagon antagonists are discussed.
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PMID:Topographical amino acid substitution in position 10 of glucagon leads to antagonists/partial agonists with greater binding differences. 869 41

Molecular cloning analysis has detected at least nine adenylate cyclase isozymes in mammalian tissues. Using fetal rat skin keratinocytes (FRSK), we investigated adenylate cyclase expression and its modulation by 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), a retinoid (Ro10-1670), and 12-O-tetradecanoylphorbol-13-acetate (TPA). Reverse transcription polymerase chain reaction (RT-PCR) indicated that FRSK contain adenylate cyclases I, II, III, IV, VI and VIII. Treatment with 1,25(OH)2D3 (1 x 10(-7) M), Ro10-1670 (1 x 10(-6) M), and TPA (100 ng/ml) resulted in increased forskolin-induced cyclic AMP accumulation by FRSK cells and normal human keratinocytes (NHK). Quantitative RT-PCR and Western blot analysis, however, detected no alteration in mRNA and protein levels of each adenylate cyclase isozyme for at least 48 h. These results indicate that FRSK contain at least six (I, II, III, IV, VI and VIII) adenylate cyclase isozyme mRNAs, suggesting a complex regulatory mechanism of cyclic AMP generation in keratinocytes. Although 1,25(OH)2D3, Ro10-1670, and TPA augmented forskolin-induced cyclic AMP accumulation, they do not seem to affect the expression of specific adenylate cyclase isozymes by FRSK cells.
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PMID:Adenylate cyclases in keratinocytes: FRSK cells express types I, II, III, IV, VI and VIII, and 1,25(OH)2D3, retinoic acid and TPA augment forskolin-induced cyclic AMP accumulation in the absence of altered isozyme expression. 976 1

Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) are two closely related peptides that bind two homologous G protein-coupled receptors, VIP/PACAP receptor 1 (VPAC1R) and VIP/PACAP receptor II (VPAC2R), with equally high affinity. Recent reports suggest that VPAC2R plays a role in circadian rhythm and T cell functions. To further elucidate the functional activities of VPAC2R, we generated VPAC2R-deficient mice by deleting exons VIII-X of the VPAC2R gene. The VPAC2R-deficient mice showed retarded growth and had reduced serum IGF-I levels compared with gender-matched, wild-type siblings. The mutant mice appeared healthy and fertile at a young adult age. However, older male mutant mice exhibited diffuse seminiferous tubular degeneration with hypospermia and reduced fertility rate. The mutant mice appeared to have an increase in insulin sensitivity. VPAC2R-deficient mice had increased lean mass and decreased fat mass with reduced serum leptin levels. Indirect calorimetry experiments showed that the respiratory quotient values immediately following the transition into the dark cycle were significantly higher in male knockout mice for about 4 h. Additionally, male and female VPAC2R-deficient mice presented an increased basal metabolic rate (23% and 10%, respectively) compared with their wild-type siblings. Our results suggest that VPAC2R plays an important role in growth, basal energy expenditure, and male reproductive functions.
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PMID:Vasoactive intestinal polypeptide/pituitary adenylate cyclase-activating peptide receptor 2 deficiency in mice results in growth retardation and increased basal metabolic rate. 1223 11

Human sperm chemotaxis is a critical component of the fertilization process, but the molecular basis for this behavior remains unclear. Recent evidence shows that chemotactic responses depend on activation of the sperm olfactory receptor, hOR17-4. Certain floral scents, including bourgeonal, activate hOR17-4, trigger pronounced Ca(2+) fluxes, and evoke chemotaxis. Here, we provide evidence that hOR17-4 activation is coupled to a cAMP-mediated signaling cascade. Multidimensional protein identification technology was used to identify potential components of a G-protein-coupled cAMP transduction pathway in human sperm. These products included various membrane-associated adenylate cyclase (mAC) isoforms and the G(olf)-subunit. Using immunocytochemistry, specific mAC isoforms were localized to particular cell regions. Whereas mAC III occurred in the sperm head and midpiece, mAC VIII was distributed predominantly in the flagellum. In contrast, G(olf) was found mostly in the flagellum and midpiece. The observed spatial distribution patterns largely correspond to the spatiotemporal character of hOR17-4-induced Ca(2+) changes. Behavioral and Ca(2+) signaling responses of human sperm to bourgeonal were bioassayed in the presence, or absence, of the adenylate cyclase antagonist SQ22536. This specific agent inhibits particulate AC, but not soluble AC, activation. Upon incubation with SQ22536, cells ceased to exhibit Ca(2+) signaling, chemotaxis, and hyperactivation (faster swim speed and flagellar beat rate) in response to bourgeonal. Particulate AC is therefore required for induction of hOR17-4-mediated human sperm behavior and represents a promising target for future design of contraceptive drugs.
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PMID:Particulate adenylate cyclase plays a key role in human sperm olfactory receptor-mediated chemotaxis. 1527 85

We previously reported that acute agonist activation of G(i/o)-coupled receptors inhibits adenylate cyclase (AC) type VIII activity, whereas agonist withdrawal following chronic activation of these receptors induces AC-VIII superactivation. Three splice variants of AC-VIII have been identified, which are called AC-VIII-A, -B and -C (with AC-VIII-B missing the glycosylation domain and AC-VIII-C lacking most of the C1b area). We report here that AC-VIII-A and -B, but not -C, are inhibited by acute mu-opioid and dopaminergic type D2 receptor activation, indicating that the C1b area of AC-VIII has an important role in AC inhibition by G(i/o)-coupled receptor activation. On the other hand the glycosylation sites in AC-VIII did not play a role in AC-VIII regulation. Although AC-VIII-A and -C differed in their capacity to be inhibited by acute agonist exposure, agonist withdrawal after prolonged treatment led to a similar superactivation of all three splice variants, with no significant change in AC-VIII expression. AC-VIII superactivation was not affected by pre-incubation with a cell permeable cAMP analogue, indicating that the superactivation does not depend on the agonist-induced reduction in cAMP levels. The superactivated AC-VIII-A, -B and -C were similarly re-inhibited by re-application of agonist (morphine or quinpirole), returning the activity to control levels. These results demonstrate marked differences in the agonist inhibition of the AC-VIII splice variants before, but not after, superactivation.
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PMID:Regulation of adenylate cyclase type VIII splice variants by acute and chronic Gi/o-coupled receptor activation. 1553 92


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