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)

A permanently transformed cell line derived from human embryo renal cortical cells (HEK293) has been investigated for the retention of renal-specific properties. The cell line is epithelioid in growth on plastic, and transmission electron microscopy demonstrates the formation of apical zonae occludentes. There is no prominent brush-border. The response of HEK293 cell adenylate cyclase is noteworthy for the response to vasoactive intestinal peptide (half-maximal activation at 0.9 nM). The HEK adenylate cyclase response to VIP is specific, with related peptides such as glucagon and secretin being ineffective. The response to VIP is competitively antagonized by the VIP receptor antagonist (4Cl-D-Phe6,Leu17)-VIP.
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PMID:A cultured human renal epithelioid cell line responsive to vasoactive intestinal peptide. 216 76

Afferent influences on natural cell death were modeled in retinal cultures derived from neonatal rats. Tetrodotoxin (TTX) blockade of electrical activity produced a significant reduction in surviving retinal ganglion cell (RGC) neurons during a critical period of development, similar in magnitude to the reduction observed during natural cell death in the intact retina at a similar developmental stage. The addition of vasoactive intestinal peptide (VIP) protected the RGCs from the lethal action of TTX. This effect was specific, since the related peptides PHI-27 and secretin produced no significant increase in RGC survival. Radioimmunoassay of cyclic nucleotides showed that TTX decreased culture levels of cAMP and that this trend was reversed by VIP. Decreases in RGC survival associated with TTX electrical blockade were prevented by 8-bromo:cAMP or forskolin. Furthermore, VIP10-28, the C-terminal fragment that inhibits VIP stimulation of adenylate cyclase, reduced the number of surviving RGCs. Thus, our results suggest that VIP, acting by increasing cAMP, has a neurotrophic effect on electrically blocked RGCs and may be an endogenous factor modulating normal cell death in the retina.
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PMID:VIP-mediated increase in cAMP prevents tetrodotoxin-induced retinal ganglion cell death in vitro. 216 72

GRF promotes follicular maturation and ovulation when administered with FSH in the treatment of infertility. Such actions could be mediated by stimulation of GH secretion and insulin-like growth factor I production, but the known actions of the structurally related hormone, vasoactive intestinal peptide (VIP), on granulosa cell function suggested that GRF may also act directly on the ovary to stimulate follicular development. Radioligand binding and activation studies, performed in granulosa cells from immature estrogen-treated rats, revealed a common receptor for VIP and rat (r) GRF in the ovary. Specific binding of [125I]VIP to granulosa cells was saturable and dependent on time and temperature. The relative potencies of VIP-related peptides for inhibition of radioligand binding were: VIP greater than rGRF greater than peptide histidine isoleucinamide greater than [His1,Nle27] human GRF(1-32)NH2 greater than secretin. In binding studies with the potent GRF agonist, [125I] [His1,Nle27]GRF(1-32)NH2, relative potencies were: rGRF(1-43)OH greater than [His1,Nle27]human GRF(1-32)NH2 greater than VIP greater than peptide histidine isoleucinamide greater than secretin. Glucagon and gastric inhibitory peptide, other peptides of the glucagon superfamily, and unrelated peptides including CRF and beta-endorphin, did not inhibit binding of either radioligand to ovarian receptors. In cultured granulosa cells, rGRF and VIP stimulated cAMP formation, consistent with coupling of their receptors to the adenylate cyclase system, and potentiated FSH-induced cAMP production. Both peptides also amplified FSH-induced progesterone biosynthesis, aromatase activity, and LH receptor formation. These observations demonstrate that rGRF is a potent cAMP-mediated agonist in the rat ovary and acts on a common VIP/GRF receptor in maturing granulosa cells. It is likely that the potentiating effect of administered GRF on gonadotropin-stimulated follicular development in vivo is in part mediated by direct actions of the peptide on the VIP/GRF receptor. Also, since GRF is present in the gonads, it is possible that the locally-produced peptide promotes follicular maturation by paracrine modulation of the stimulatory action of FSH on granulosa cell function.
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PMID:Receptor-mediated actions of growth hormone releasing factor on granulosa cell differentiation. 217 7

Secretin receptors in membranes from the neuroblastoma-glioma hybrid cell line NG108-15 were investigated by 125I-secretin binding and adenylate cyclase activation. On both parameters the corresponding relative potencies of parent peptides were, respectively: secretin greater than helodermin greater than peptide histidine isoleucinamide = vasoactive intestinal peptide. With secretin analogs and secretin fragments, the order of potency for binding was: secretin = [Val5]secretin greater than [Ala2]secretin = [Ala11]secretin greater than [Ala4, Val5] secretin greater than [Ala4]secretin greater than [D-Phe4] secretin greater than [D-Phe2]secretin = secretin (2-27) greater than secretin (3-27) greater than secretin (7-27). Also, on adenylate cyclase, [D-Phe4]secretin, [D-Phe2]secretin, secretin (2-27) and secretin (3-27) were partial agonists while secretin (7-27) was ineffective. The differentiating agent N6,2'-O-dibutyryladenosine 3',5'-monophosphate (1 mM) increased the density of secretin receptors and secretin-stimulated adenylate cyclase activity after a lag period of 4 h. After incubation for 24 h, receptor number and enzyme activity were increased 4- and 3-fold, respectively. These effects were inhibited totally by 1 microgram/ml cycloheximide and halved by 5 micrograms/ml actinomycin D. They were mimicked by 1 mM sodium butyrate but were not reproduced by either 8-bromoadenosine 3',5'-monophosphate or the phosphodiesterase inhibitor rac-4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone.
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PMID:Secretin receptors in the neuroglioma hybrid cell line NG108-15. Characterization and regulation of their expression. 217 30

We investigated the ability of two forms of Pituitary Adenylate Cyclase Activating Polypeptide [PACAP-38, the 38 amino acid peptide isolated from ovine hypothalamus, and PACAP-27, a shorter N-terminal (1-27) amidated version] to interact with specific receptors in membranes from the human neuroblastoma cell line NB-OK. [125I]PACAP-27 bound rapidly and specifically to one class of high affinity sites (Kd 0.5 nM). VIP inhibited [125I]PACAP-27 binding 300- to 1000-fold less potently than PACAP-27 and PACAP-38. One microM PHI prevented tracer binding only partially and secretin, glucagon and GRF(1-29)NH2 were ineffective in this respect. PACAP-27 and PACAP-38 stimulated adenylate cyclase activity dose dependently and with similar efficacy (Kact 0.2-0.3 nM), this activation being compatible with the occupancy of specific high affinity PACAP receptor. VIP was markedly less potent and less efficient on this enzyme than PACAP. Chemical cross-linking of [125I]PACAP-27 followed by SDS-PAGE and autoradiography revealed specific cross-linking with a 68 kDa protein.
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PMID:The novel VIP-like hypothalamic polypeptide PACAP interacts with high affinity receptors in the human neuroblastoma cell line NB-OK. 217 43

The authors examined the effect of topical application of agents known to increase cyclic nucleotide levels on tear secretion by accessory lacrimal gland tissue in their rabbit model for keratoconjunctivitis sicca (KCS). Tear secretion was studied by changes in tear film osmolarity and tear volume caused by application of the agents relative to application of isotonic buffer solution alone. A decrease in tear film osmolarity or increase in tear volume was interpreted as an increase in tear secretion. Irritative stimulation was distinguished from pharmacologic stimulation by the prior use of topical proparacaine. The following agents significantly decreased tear film osmolarity and increased tear volume: vasoactive intestinal peptide (2 X 10(-8) to 2 X 10(-6) M); three pro-opiomelanocortin fragments alpha-, beta-, and gamma-melanocyte stimulating hormone at 10(-4), 10(-3), and 10(-3) M, respectively; the permeable cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) analogs 8-Br cAMP (0.3-3.0 X 10(-3) M) and 8-Br cGMP (1.0-10.0 X 10(-3) M); and the cyclic nucleotide phosphodiesterase inhibitor 1-isobutyl-3-methyl xanthine (0.3-3.0 X 10(-3) M). Forskolin (2 X 10(-4) M), which activates the catalytic subunits of adenyl cyclase, increased tear volume significantly. Secretin, adrenocorticotropic hormone, and pilocarpine were ineffective. The authors conclude that agents that increase either cAMP or cGMP levels pharmacologically stimulated tear secretion when applied topically to rabbit eyes with surgically induced KCS.
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PMID:Stimulation of tear secretion by topical agents that increase cyclic nucleotide levels. 236 69

Forskolin stimulated adenylate cyclase activity 55-fold in crude rat pancreatic plasma membranes. Dose-response curves were better fitted by a two-component model with apparent Ka for forskolin of 0.8 microM and 85 microM corresponding, respectively, to 15% and 85% of total activity. Gpp (NH)p alone or the combined presence of GTP plus a hormone (secretin, VIP or CCK-8) potentiated activation through the high affinity forskolin component. These results are in favour of a dual mode of action of forskolin: a high affinity component related to the stimulatory guanine nucleotide-binding regulatory subunit, and a low affinity component more closely related to the catalytic subunit of the enzyme. In dispersed rat pancreatic acini, forskolin increased cyclic AMP levels 26-fold and potentiated the increase induced by secretin, VIP, and CCK-8. It also stimulated the phosphorylation of three particulate proteins (Mr = 21K, 25K and 33K). In terms of secretion, it raised amylase secretion by 60%, a weak effect comparable to that exerted by VIP but much lower than that of secretin or CCK-8. Forskolin did, however, potentiate the secretory effect of CCK-8 (a hormone inducing a redistribution of cellular calcium) while being without influence on the secretory effects of secretin and VIP.
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PMID:Effects of forskolin on adenylate cyclase activity and amylase secretion in the rat exocrine pancreas. 241 Apr 66

In rat pancreatic acinar tissue adenylate cyclase is stimulated by low concentrations of secretin, while higher concentrations also activate phosphatidylinositol bisphosphate hydrolysis. By the use of the secretin analogues [Tyr10,13]secretin and [Tyr10,13,Phe22,Trp25]secretin, we have shown that substitution of tyrosine for leucine at positions 10 and 13 was sufficient to reduce the ability of the peptide to stimulate the production of inositol trisphosphate and the increases in cytosolic free calcium, while the ability to stimulate cAMP is little affected and the peptide remained a full agonist. Incubation with cholera toxin caused increases in cAMP, which were maximal after 30 min. Cholera toxin treatment also resulted in a marked reduction of secretin-stimulated inositol trisphosphate production, but this required a much more prolonged treatment (150-240 min), suggesting that different cholera toxin substrates were involved. Activation of protein kinase C with the phorbol ester phorbol 12-myristate 13-acetate had no effect on secretin-induced cAMP formation, nor was secretin-stimulated inositol trisphosphate formation altered by further increases in cAMP. These results indicate that the mechanisms by which secretin stimulates adenylate cyclase and activates phospholipase C in acinar tissue are completely independent.
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PMID:Secretin stimulates cyclic AMP and inositol trisphosphate production in rat pancreatic acinar tissue by two fully independent mechanisms. 243 75

We have demonstrated the existence of two types of hormone-responsive adenylate cyclase in the isolated perfused rat liver. One, less abundant, is linked to glycogenolysis and the other is not. Glucagon stimulates mainly the glycogenolysis-linked fraction and, to a lesser extent, the fraction which is not linked to glycogenolysis. The suppressive effect of insulin is specific for the glucagon-responsive adenylate cyclase and is inhibited by 3-isobutyl-1-methylxanthine (IBMX). However, this mechanism can explain only partly the ability of insulin to suppress glycogenolysis, and is not observed when cAMP is increased sufficiently by glucagon. Secretin-responsive adenylate cyclase is not linked to glycogenolysis and is suppressed specifically by oxymetazoline. The capacity of this suppressive effect is large and not inhibited by IBMX. These results suggest that there is a functional compartmentalization of cAMP within the hepatocyte or among hepatocytes.
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PMID:Two types of hormone-responsive adenylate cyclase in the rat liver. 244 65

Membrane currents were recorded from voltage-clamped Xenopus laevis oocytes, surrounded by their enveloping follicular and epithelial cells. Porcine vasoactive intestinal peptide (VIP) generated a membrane current due to an increase in membrane conductance to K+. The VIP current was mimicked by the adenylate cyclase activator forskolin and was potentiated by phosphodiesterase inhibitors, suggesting that adenosine 3',5'-cyclic monophosphate (cyclic AMP) plays a role in mediating the response. Though resembling the follicle's responses to catecholamines and adenosine in ionic basis and apparent mechanism, the response to VIP was not blocked by catecholaminergic or purinergic antagonists, indicating the presence of a specific VIP receptor in the follicle. Among the VIP related peptides, PHM-27 generated similar but smaller K+ currents and porcine secretin and glucagon neither elicited a response nor blocked that to VIP. After treating follicles with collagenase to remove the epithelial and follicular cells the responses to VIP were either substantially reduced or abolished, suggesting that the VIP receptors and K+ channels are both located in the follicular cells.
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PMID:Membrane currents elicited by porcine vasoactive intestinal peptide (VIP) in follicle-enclosed Xenopus oocytes. 244 88


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