Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin decreased markedly the adenylyl cyclase activity associated with fat cell membranes purified by centrifugation in sucrose gradients. The hormone effect was not readily evident in crude membrane preparations. The kinetics of this effect indicate that some time was required for the onset of the insulin-induced inactivation. This lag period decreased when the insulin concentration was increased. The hormone dose dependence for adenylyl cyclase inactivation measured at a fixed time (3 min) showed a 10 to 15% decrease in activity at 1 to 30 muU per ml insulin; 30 to 40% at 100 to 1000 muU per ml; and 75% at 0.1 U per ml. The insulin effect was completely abolished by 0.1 mM GMP-P(NH)P, 10mM fluoride, or 50 ng per ml glucagon, or by increasing the Mn++ concentration to 4 mM. In addition, it was partially reversed by the addition of a fraction from the sucrose gradient, which contained soluble factors. The kinetics of the adenyl cyclase-catalyzed reaction were studied using ATP or AMP-P(NH)P as adenylyl donor, and Mn++ or Mg++ as divalent cation, in the absence or presence of insulin. With ATP and Mg++ there was a striking reduction of the transient reaction rates after 1.5 min of incubation. Under these conditions the insulin effect was not evident. On the contrary, with ATP and Mn++ this spontaneous reduction of activity was less evident; however, in the presence of insulin there was a clear and marked reduction of the transient reaction rate measured after 1.5 min of incubation. With AMP-P(NH)P the kinetic data were qualitatively similar to those observed with ATP. It is concluded that under certain assay conditions adenylyl cyclase may be converted to an inactive enzyme form, and that such a conversion is more evident in the presence of Mg++ than with Mn++. In the latter case, insulin appears to enhance the rate of this conversion.
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PMID:Effects of insulin on the adenylyl cyclase activity of isolated fat cell membranes. 70 24

The basal adenylate cyclase activity of the rat heart increases with the age of the animal. By itself, 10(-5) M glucagon activates only adenylate cyclase activity from adult rat hearts. In contrast, 10(-5) M glucagon in the presence of 10(-4)M 5'-guanylylimidodiphosphate (GMP-PNP) clearly activates adenylates cyclase activity in the 14-day-old rat heart, with some activation being evident in hearts of 7-day-old animals. GMP-PNP, 10(-4) M, activates adenylate cyclase activity by itself at ages of 14 days and older, but to a far lesser degree than in combination with 10(-5) M glucagon. Activity elicited by NaF increases throughout the neonatal period. The ratio of NaF-stimulated activity to basal activity increases from 6.3 at 2 days to 10.0 in the adult, a change which is not statistically significant. We conclude that a cardiac receptor for glucagon is present early in neonatal period of the rat, but this receptor cannot effect activation of adenylate cyclase and an increase in heart rate, or depletion of glycogen. Even in the presence of 10(-4) GMP-PNP, the response to glucagon by cardiac adenylate cyclase depends on the age of the rat. In heart cells from a 7-day-old rat, the response is barely measurable but the magnitude of the response increases each week.
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PMID:Development of guanylylimidodiphosphate-dependent activation of adenylate cyclase by glucagon in the neonatal rat heart. 97 86

The effects of various nucleosides and nucleotides upon glucagon secretion from the isolated perfused rat pancreas were studied. Increasing glucagon secretion was found with increasing concentrations of exogenous cyclic AMP (2 X 10(-4) M, 2 X 10(-3) M and 1 X 10(-2) M). Stimulation of alpha cell secretion was also found with 2 X 10(-3) M 2'AMP, 3'AMP, 5'AMP, ADP, Adenosine, NADP, and NADPH. One X 10(-3) M cyclic GMP elicited significant glucagon secretion. The pattern of glucagon release was similar in all cases with peak secretion occurring during the 30- to 90-s time period following initiation of the stimulus. No significant increase of glucagon secretion was found in response to ATP, guanosine, 2'GMP, 3'GMP, 5'GMP, GTP, xanthosine, inosine, adenine, xanthine, thymidine, cytidine, ribose, nicotinamide, and uric acid. On the basis of the above results, the structural requirement for stimulation of glucagon secretion appears to be adenine linked to ribose, with phosphate groups being unnecessary. The conclusion of this study is that a new class of compounds capable of stimulating glucagon secretion has been identified, and important questions are thus raised about the mechanism of the action of exogenous cyclic AMP.
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PMID:Nucleotide and nucleoside stimulation of glucagon secretion. 110 53

Glucagon and adrenaline exert their action upon the liver via the cyclic AMP synthetizing system located in the plasma membrane. The enzyme adenylate cyclase is further regulated by guanyl nucleotides. It has been recently shown that the rat liver plasma membrane system could respond to GTP by simultaneous increase in the cyclase activity in response to glucagon and by the dissociation of this hormone from its binding sites (1). Unambiguous relationship between the activating effect of GTP upon the cyclase and its action upon glucagon binding has not been determined yet (2). This problem was approached using the in vitro action of epinephrine as a model. When 1 to 100 muM GTP or DGP were added to rat liver plasma membranes isolated from adrenalectomized animals, they increased markedly the response of the cyclase system to epinephrine. These effects could be observed in the absence of an ATP-regenerating system and were mimicked by 5'-guanylyl diphosphonate; GTP and GDP were the most active compounds followed by ITP, CTP and by a series of guanyl derivatives. UTP, as well as guanosine, GMP, cyclic GMP and ppGpp were inactive. Guanyl nucleotides did not increase the affinity of the cyclase system for the activating hormones, but enhanced the affinity for ATP-Mg and also the Vmax of the reaction. Finally, GTP, ATP, CTP, UTP but not GDP displaced epinephrine bound to plasma membranes by a mere chelation phenomenon. It is concluded that 1) guanyl nucleotides do not act primarily by influencing the binding of hormones to the membranes; 2) they act directly upon the catalytic subunit of the cyclase; 3) the low concentrations of GTP required for its action strongly suggest that this nucleotide plays a role in the physiological regulation of the intrahepatic cyclic AMP level.
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PMID:[Role of guanidylic nucleotides in the adenylate cyclase activity of the rat liver]. 120 15

Glucagon, a peptide hormone synthesized and secreted by alpha islet cells, regulates glucose homeostasis by several mechanisms. Using [gamma 32P]8N3GTP, a proven photoaffinity probe for GTP, a specific nucleotide binding site on human glucagon was detected that showed preference for GTP. Half-maximal saturation of photoinsertion into the polypeptide hormone was at 8-12 microM with either [alpha 32P]8N3GTP or [gamma 32P]8N3GTP. GTP protected photolabeling with an apparent kd of 15 microM, whereas ATP was less effective as a protector, exhibiting an apparent kd of about 30 microM. Maximal protection by GTP and ATP was over 90%. UTP, CTP, GDP, ADP, GMP, AMP, guanosine, adenosine, guanine, and adenine were much less effective protectors, indicating that binding is specific for purine nucleoside triphosphates, particularly GTP. Mg2+ at 150 microM enhanced photoinsertion (twofold), whereas at 2-10 mM, it inhibited photoinsertion. Both Ca2+ and Zn2+ at 0.2 mM decreased photoinsertion about 45%. Purification of chymotryptic and tryptic digests of photolabeled glucagon by reverse-phase high performance liquid chromatography (HPLC) revealed that the N-terminal peptide, HSQGTF, was the only peptide region covalently photomodified by [32P]8N3GTP. GTP, if present during photolysis, greatly reduced both photoinsertion into glucagon and the amount of radiolabeled peptide recovered on HPLC. The specificity of binding to the N-terminal region is suggestive of a physiological role for a glucagon-GTP complex in the mechanism of action of this hormone.
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PMID:Identification of the guanine binding domain peptide of the GTP-binding site of glucagon. 130 73

Identification of hormone target sites in the nephron has been achieved in part using autoradiography, and largely with microdissection and microanalysis techniques that permit quantitative measurements of hormone binding or postbinding effects in discrete nephron segments. The nephron target sites of hormones whose intracellular second messenger is known have been located by measuring their stimulatory effect on cyclic AMP or GMP production along the nephron. These hormones include arginine vasopressin, parathyroid hormone, calcitonin, and beta-adrenergic catecholamines. In contrast, the action sites of hormones whose cellular mediators are less well understood have been identified using micro modifications of conventional binding techniques scaled down to the minute (less than or equal to 1 microgram protein) amount of tissue available. In this group are aldosterone, corticosterone, insulin, angiotensin II, alpha-adrenergic catecholamines and dopamine. Atrial natriuretic peptides and glucagon have been studied with both methods. The precise localization of hormone receptors and sites of action in the functionally heterogeneous nephron is critical for understanding the interactions between the kidney and the endocrine system in fluid volume homeostasis, blood pressure control, and in biochemical and metabolic regulation.
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PMID:Hormone receptors and sites of action in the kidney. 132 67

The vasoactive intestinal peptide (VIP) receptors were identified on the membranes from the rat anterior pituitary gland with [125I]VIP. The dissociation constant (Kd) and the maximal binding capacity (Bmax) values were estimated from the competitive inhibition data. The Kd and Bmax values were 1.05 +/- 0.75 nM and 103 +/- 11 fmol/mg protein, respectively. The order of molar potency of related peptides to inhibit [125I]VIP binding was VIP greater than peptide histidine isoleucine (PHI) greater than secretin greater than glucagon. Glucagon was not effective to inhibit the binding. [125I]VIP binding was effectively inhibited by the addition of guanine nucleotides. The order of molar potency to inhibit the binding was Gpp(NH)p greater than GTP greater than GDP greater than GMP greater than ATP. These results directly suggest the coupling of VIP receptors with guanine nucleotide binding proteins in the anterior pituitary gland.
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PMID:Direct demonstration of guanine nucleotide sensitive receptors for vasoactive intestinal peptide in the anterior lobe of the rat pituitary gland. 216 81

To investigate whether guanine nucleotides regulate interconversion of the two-state hepatic glucagon receptor we have utilized kinetic assays of glucagon binding to partially purified rat liver plasma membranes. Dissociation of glucagon at 30 degrees C exhibited biexponential character in either the absence or presence of GTP, indicating that the system previously seen in intact hepatocytes is independent of intracellular modulators. In each case the receptors underwent a time-dependent conversion from a low affinity to a high affinity state. However, GTP decreased the fraction of receptors in the high affinity state. The rank order for stabilizing the low affinity state was Gpp(NH)p greater than GTP greater than GDP much greater than GMP = no nucleotides. Data from competition binding assays with increasing concentrations of GTP allow calculation of equilibrium constants which are 3.32 nM for glucagon and receptor in the absence of GTP, 18.6 nM for glucagon and receptor in the presence of GTP, 1.55 microM for the association of receptor and GTP presumably linked to an N protein, and 8.86 microM for the association of the glucagon-receptor complex and GTP again presumably linked to an N protein, Glucagon binding to receptor is noncooperative in both the absence and presence of GTP, distinguishing this system from the beta-adrenergic system. With GTP, binding to the low affinity state is favored because of the relative affinities reported. Therefore, GTP regulates the activation by slowing the conversion of the receptor from a low affinity to high affinity form.
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PMID:Guanine nucleotide regulation of the interconversion of the two-state hepatic glucagon receptor system of rat. 283 9

The effects of Mg2+ and guanine nucleotides on glucagon binding to its receptor were studied using [125I-Tyr10]monoiodoglucagon. Contrary to findings with beta-adrenergic receptors, high affinity binding of the stimulatory hormone was not dependent on Mg2+ and low affinity binding could be obtained on nucleotide addition regardless of presence of Mg2+. GDP, guanyl-5'-yl thiophosphate (GDP beta S), GTP, and guanyl-5'-yl imidodiphosphate (GMP-P(NH)P) were all able to induce low affinity hormone binding. Since the Ns component of adenylyl cyclase, with which the receptor interacts, is inactive in stimulating the catalytic component C of adenylyl cyclase in the absence of Mg2+, both before and after GDP addition, it is suggested that Ns has at least two domains that change conformation independently of each other: a r domain, that interacts with the receptor and confers to it high affinity binding, and a c domain, that interacts with the catalyst C and stimulates it. It is suggested further that Ns is r+c- when stabilizing the receptor in its conformation with high affinity for hormone, and r-c- when under the influence of GDP which results in the receptor adopting the conformation that exhibits low affinity for the hormone. Comparison of potencies of the four nucleotides to induce low affinity binding showed that GDP and GDP beta S were equipotent and 10 times more potent than GTP and 100 times more potent than GMP-P(NH)P. Under the conditions used it was impossible to substantiate that the effects of GTP or GMP-P(NH)P were not due to formation of GDP from GTP or presence of GDP-like material in GMP-P(NH)P. It is suggested that, contrary to widely held opinions, GDP and GDP-like compounds, and not GTP or its analogs, are responsible for the lowering of the affinity of adenylyl cyclase stimulating receptors for their hormones or agonists. Furthermore, the experiments suggest that the c+ conformation of the c domain of Ns co-exists with the r+ and not the r- conformation of its r domain.
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PMID:Regulation of glucagon receptor binding. Lack of effect of Mg and preferential role for GDP. 298 62

Adenylate cyclase activity was studied in the myocardial sarcolemma and aorta of spontaneously-hypertensive rats (SHR) and their respectively Wistar-Kyoto (WKY) controls. Basal enzyme activity was decreased in the SHR as compared to the WKY group. Adenylate cyclase stimulation by N-ethylcarboxamide adenosine (NECA) was significantly lower in the myocardial sarcolemma and aorta of SHR, and this decreased responsiveness was associated with a reduction in the Vmax. Other agonists, such as isoproterenol (ISO), epinephrine, dopamine (DA), and glucagon, also enhanced myocardial adenylate cyclase activity to various degrees in SHR and WKY, but stimulation (Vagonists/Vbasal) was always lower in the SHR. NaF and forskolin (FSK), which activate adenylate cyclase via receptor-independent mechanisms, augmented it in the myocardial sarcolemma of SHR to a lesser extent than in WKY. While the guanine nucleotides GTP and GMP-P(NH)P elevated adenylate cyclase in a concentration-dependent manner in both SHR and WKY, the magnitude of stimulation was significantly lower in the former group. Decreased basal adenylate cyclase activity and responsiveness to adenosine, various hormones, NaF and FSK were observed in SHR of all ages, i.e. from 4 to 24 weeks of age. In addition, basal, hormone-, NaF- and FSK-stimulated adenylate cyclase activity was diminished markedly in the aorta of SHR. These results suggest that, in SHR, not only is basal adenylate cyclase activity decreased but the abilities of adenosine, other hormones and agonists, such as NaF and FSK, to stimulate adenylate cyclase, guanine nucleotide regulatory protein and the catalytic subunit of the cyclase system are also impaired in the myocardial sarcolemma and aorta.
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PMID:Altered responsiveness of adenylate cyclase to adenosine and other agents in the myocardial sarcolemma and aorta of spontaneously-hypertensive rats. 339 77


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