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)

Amylin binding sites in a human hepatoblastoma cell line (HepG2) have been characterized in detail. 125I-Amylin (rat) bound to HepG2 cells with high affinity. Binding was reversible and selective, and dependent on time and temperature. Scatchard analysis revealed the presence of high (Kd = 0.11 +/- 0.04 nM) and low (Kd = 1.3 +/- 0.4 microM) affinity binding sites for 125I-amylin in HepG2 cells. The dissociation experiments also showed that 125I-amylin dissociated from high- and low-affinity sites. The association data, however, indicated the presence of only one binding site. Rat amylin was more potent than human amylin and rat calcitonin gene-related peptide (CGRP) in displacing 125I-amylin bound to HepG2 cells. Nonhomologous peptides did not displace 125I-amylin. Rat amylin was, however, less potent than rat CGRP in displacing 125I[Tyr0]CGRP from HepG2 cells. Pretreatment of HepG2 cells with rat amylin (10 nM) reduced the specific binding of 125I-amylin by 75%, whereas rat CGRP (10 nM) pretreatment had no effect on amylin binding. Calcitonin gene-related peptide, as well as rat and human amylin, stimulated the adenylate cyclase activity of HepG2 cell membrane preparation in a dose-dependent manner, with an order of potency of CGRP > rat amylin > human amylin. A CGRP antagonist, CGRP(8-37), significantly attenuated the stimulatory effect of both amylin and CGRP on adenylate cyclase activity. These investigations show that distinct receptors of amylin and CGRP are present in HepG2 cells, and that amylin stimulates adenylate cyclase activity through CGRP receptors. This system could now be exploited for studying amylin receptors and amylin-mediated signal transduction.
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PMID:Characterization of amylin binding sites in a human hepatoblastoma cell line. 133 79

The CHO-K1 cell line responds to the peptide amylin by a rapid elevation of cAMP. The related peptide calcitonin gene-related peptide (CGRP) is 100 times less potent at stimulating adenylate cyclase than is amylin. The actions of amylin at this receptor are concentration dependent and not antagonized by the CGRP antagonist CGRP-(8-37). Although these cells have receptors for calcitonin, amylin is unable to take part in any high affinity interaction with these receptors, as assessed by radioligand binding. The CHO-K1 cell line has receptors for amylin that are distinct from those for calcitonin and CGRP.
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PMID:Stimulation of adenylate cyclase by amylin in CHO-K1 cells. 137 16

In this study, we compared the effects of islet amyloid polypeptide (IAPP) and calcitonin gene-related peptide (CGRP) on glucose metabolism both in vivo and in vitro in the rat. Intravenous injection of rat CGRP caused a significant increase in plasma glucose concentration with a simultaneous increase in plasma insulin levels, whereas neither IAPP-NH2 nor IAPP-COOH had any effect. Moreover, intravenous infusion of CGRP decreased tolerance to intragastric administration of glucose (O-GTT) without altering plasma insulin levels, but again IAPPs had no effect. On the other hand, 125I-[Tyr0]rat CGRP specifically bound to the liver plasma membrane, and not only CGRP but also IAPP-NH2 dose-dependently displaced the specific binding of 125I-[Tyr0] CGRP, whereas IAPP-COOH had no effect. Conversely, CGRP as well as IAPP-NH2 but not IAPP-COOH evoked dose-dependent activation of adenylate cyclase in the membranes, and these effects were significantly inhibited by a CGRP receptor antagonist, human CGRP-I(8-37). However, neither CGRP nor IAPP-NH2 had any effect on glucose production in rat isolated hepatocytes. These results suggest that (1) IAPP-NH2 but not IAPP-COOH induces adenylate cyclase activation via CGRP receptors on rat liver plasma membranes, and (2) CGRP might not involve its action on the liver in the changes of glucose metabolism.
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PMID:Effects of islet amyloid polypeptide (amylin) and calcitonin gene-related peptide (CGRP) on glucose metabolism in the rat. 154 Dec 37

Both human and rat islet amyloid polypeptide with COOH-terminal amide (IAPP-NH2) dose-dependently displaced the specific binding of 125I-labeled [Tyr0] rat alpha-calcitonin gene-related peptide (CGRP) to rat liver plasma membranes, whereas human IAPP (IAPP-COOH) had no effect. Conversely, human or rat IAPP-NH2 but not human IAPP-COOH evoked dose-dependent activation of adenylate cyclase in the membranes, and these effects were significantly inhibited by the CGRP-receptor antagonist human CGRP-1(8-37). Moreover, the dose of human or rat IAPP-NH2 necessary for producing half-maximal activation of adenylate cyclase was comparable with that for producing a half-maximal inhibition of the label binding. Thus, IAPP-NH2 but not IAPP-COOH appears to induce adenylate cyclase activation via CGRP receptors on rat liver plasma membranes.
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PMID:Activation of adenylate cyclase by islet amyloid polypeptide with COOH-terminal amide via calcitonin gene-related peptide receptors on rat liver plasma membranes. 216 4

Amylin inhibits glucose-induced insulin secretion in the rat pancreas. To study the mechanism by which amylin acts on the B-cell, we have investigated, in the perfused rat pancreas, the effect of synthetic rat amylin (75 pM) on insulin release elicited by secretagogues acting on the B-cell via the adenylate cyclase/cAMP system, i.e., glucagon (10 nM), gastric inhibitory polypeptide (GIP, 1 nM), forskolin (1 microM) and isobutylmethylxanthine (IBMX, 75 microM). In addition, we examined the effect of amylin on GIP-induced insulin release in pancreata from rats pretreated with pertussis toxin, an agent which inactivates certain Gi proteins coupled to adenylate cyclase. Amylin inhibited the insulin response to glucagon (approx. 70%), GIP (approx. 90%), IBMX (approx. 75%) as well as the early phase of forskolin-induced insulin output (approx. 74%). However, amylin failed to modify GIP-induced insulin release in pancreata obtained from pertussis toxin pretreated rats. These results would indicate that the inhibitory effect of amylin on insulin secretion could be, at least in part, attributed to its interfering with the adenylate cyclase/cAMP system. Furthermore, prevention of the inhibitory effect of amylin on GIP-induced insulin output by pertussis toxin pretreatment, supports the concept that amylin can inhibit insulin release via a pertussis toxin-sensitive Gi protein coupled to the adenylate cyclase system.
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PMID:Amylin (islet amyloid polypeptide) inhibition of insulin release in the perfused rat pancreas: implication of the adenylate cyclase/cAMP system. 751 1

We report here our investigation of the role of cyclic AMP (cAMP) in amylin signal transduction in isolated strips of soleus muscle. Rat amylin, at 100 nM, increased cAMP levels, from 0.431 +/- 0.047 to a peak of 1.24 +/- 0.01 pmol cAMP/mg wet wt. after 5 min, in the absence of added phosphodiesterase inhibitor. The EC50 of the response was 0.48 nM (+/- 0.12 log units) in the absence of insulin and 0.3 nM (+/- 0.18 log units) in the presence of 7.1 nM insulin. The response seen with a maximally effective concentration of amylin (10 nM) was similar to that seen with a maximally effective concentration of epinephrine (1 microM) under the same conditions. Consistent with the observed rise in cAMP there was an increase in glycogen phosphorylase a (EC50 2.2 nM +/- 0.25 log units), decreased glycogen content (EC50 0.9 nM +/- 0.22 log units) and enhanced production of lactate (EC50 1.5 nM +/- 0.33 log units). These data support the concept that amylin promotes glycogenolysis in skeletal muscle and enhances production of lactate through glycolysis as a result of activation of Gs coupled receptors, stimulation of adenylate cyclase, elevation of cAMP levels and activation of glycogen phosphorylase.
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PMID:Dose-dependent elevation of cyclic AMP, activation of glycogen phosphorylase, and release of lactate by amylin in rat skeletal muscle. 754 30

Stable transfectants expressing a recombinant human calcitonin receptor respond to calcitonin via increased cyclic adenosine 3',5' monophosphate (cAMP, EC50 = 0.06 nM salmon calcitonin [sCT]) and a transient mobilization of intracellular calcium ([Ca2+]i) coincident with turnover of inositol phosphate (IP; EC50 = 6 nM sCT). Millimolar increases in extracellular calcium ([Ca2+]o, EC50 = 8 mM) cause a rapid elevation in [Ca2+]i after a calcitonin dose-dependent pretreatment of cells (pretreatment EC50 = 0.2 nM sCT). Cells exhibit persistent sensitivity to increased [Ca2+]o up to 3 h after hormone exposure and even after multiple cycles of increased [Ca2+]o followed by wash. Calcitonin pretreatment of cells also allows apparent influx of elevated extracellular strontium and manganese, but little or no effect is observed on addition of barium, cadmium, or lanthanum. Human amylin (100 nM) causes a rapid and transient increase in [Ca2+]i comparable to that of calcitonin; however, no significant response to increased [Ca2+]o is observed after amylin addition. Human calcitonin gene-related product (hCGRP) (300 nM) and forskolin do not increase [Ca2+]i or activate a sensitivity to increased [Ca2+]o. Nevertheless, human amylin and human calcitonin gene-related product (hCGRP) activate adenylate cyclase with EC50s of 0.7 nM and 8 nM, respectively. The calcium-channel drugs verapamil, BAY K 8644, diltiazem, and nifedipine have little effect on [Ca2+]i increases. The calcitonin-induced transient mobilization of calcium is inhibited by treatment of cells with cholera toxin or 8-(diethylamino)-octyl-3,4,5-trimethoxybenzoate (TMB-8); whereas, the response to subsequent increased [Ca2+]o is inhibited by lanthanum chloride (200 microM) and lower pH (6.0).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Intracellular calcium increases mediated by a recombinant human calcitonin receptor. 761 Sep 22

The effect of human adrenomedullin on cerebral circulation was investigated in dogs in vivo and in vitro. Bolus administration of adrenomedullin or its homologous peptides, calcitonin gene-related peptide (CGRP) and amylin, into the vertebral artery induced a dose-dependent increase in vertebral blood flow. The potencies of adrenomedullin and CGRP were similar and approximately 100 times more than that of amylin. The effects of adrenomedullin and CGRP were inhibited by CGRP8-37, an antagonist of CGRP. In contrast to substance P, adrenomedullin did not induce an increase in blood flow after prior administration of CGRP. Pretreatment with either NG-nitro-L-arginine methyl ester or indomethacin did not affect the adrenomedullin-induced increase in blood flow. Intracisternal administration of adrenomedullin induced dilation of the basilar and other major cerebral arteries in a dose-dependent manner, accompanied by an increase in the concentration of cyclic AMP in the cerebrospinal fluid. Adrenomedullin also induced relaxation of isolated basilar and middle cerebral arterial rings. These data suggest that adrenomedullin induces vasodilation of cerebral arteries and an increase in vertebral blood by acting at CGRP receptors positively coupled to adenylate cyclase, and that these effects are not dependent on nitric oxide or prostaglandin formation.
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PMID:Effects of adrenomedullin, calcitonin gene-related peptide, and amylin on cerebral circulation in dogs. 767 75

Challenge of intact hepatocytes with amylin only succeeded in elevating intracellular cyclic AMP levels and activating phosphorylase in the presence of the cAMP phosphodiesterase inhibitor IBMX. Both amylin and CGRP similarly activated adenylate cyclase, around 5-fold, although approximately 400-fold higher levels of amylin were required to elicit half maximal activation. Amylin activated adenylate cyclase though apparently simple Michaelien kinetics whereas CGRP elicited activation by kinetics indicative of apparent negative co-operativity. Use of the antagonist CGPP(8-37) showed that both CGRP and amylin activated hepatocyte adenylate cyclase through a common receptor by a mnemonical mechanism where it was proposed that the receptor co-existed in interconvertible high and low affinity states for CGRP. It is suggested that this model may serve as a paradigm for G-protein linked receptors in general. Amylin failed to both stimulate inositol phospholipid metabolism in hepatocytes and to elicit the desensitization of glucagon-stimulated adenylate cyclase. Amylin did, however, elicit the phosphorylation of the inhibitory guanine nucleotide regulatory protein Gi-2 in hepatocytes and prevented the action of insulin in reducing the level of phosphorylation of this G-protein.
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PMID:Regulation of hepatocyte adenylate cyclase by amylin and CGRP: a single receptor displaying apparent negative cooperatively towards CGRP and simple saturation kinetics for amylin, a requirement for phosphodiesterase inhibition to observe elevated hepatocyte cyclic AMP levels and the phosphorylation of Gi-2. 792 19

We have recently cloned CTRs from cDNA libraries prepared from porcine renal and human ovarian cell lines. In situ hybridization and Northern analysis confirm the widespread distribution of CTR mRNA in numerous tissues. Hydropathy plots of the predicted amino acid sequence of the receptors demonstrate multiple hydrophobic regions that could generate 7 transmembrane spanning domains, similar to other G protein-coupled receptors. Searches of databanks for proteins with related amino acid sequences reveals that the CTRs are closely related to the receptors for parathyroid hormone/parathyroid hormone related peptide, secretin, vasoactive intestinal peptide, growth hormone releasing hormone, glucagon-like peptide-1 and glucagon. These receptors have no significant sequence homology to other G protein-coupled receptors, and therefore, appear to comprise a distinct receptor family. Expression of the hCTR or pCTR in COS cells results in expression of high affinity CTRs which are coupled to adenylate cyclase (AC). The hCTR, however, demonstrates higher affinity for human and salmon CT compared to the pCTR. Both CTRs demonstrate low affinity binding and AC activation in response to calcitonin gene related peptide, amylin or secretin, providing a possible explanation for the cross-reactivity among these peptides in vivo. Stable transfectants expressing the pCTR increase cAMP levels and increases in cytosolic free Ca2+ concentration consistent with dual coupling to AC and phospholipase C. Additional studies will help to establish the structural basis for this functional property as well as the evolutionary relationship of the members of this newly identified family of receptors.
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PMID:Characterization of the structural and functional properties of cloned calcitonin receptor cDNAs. 822 1


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