UNIPROT:P01275 - FACTA Search

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Query: UNIPROT:P01275 (glucagon)
26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, is subject to regulation by the cAMP as well as the calcium and cGMP second messenger systems. Treatment of intact rat PC12 cells with neuropeptides including secretin and vasoactive intestinal polypeptide (VIP) stimulated tyrosine hydroxylase activity 2 to 3-fold in vitro. Secretin (EC50 = 10 nM) was about 3 orders of magnitude more potent than VIP (EC50 = 3 microM). A combination of several protease inhibitors failed to enhance the potency of either peptide. Other members of the secretin family including glucagon and peptide histidine isoleucine (PHI) stimulated tyrosine hydroxylase activity to a lesser extent. Somatostatin, which is not homologous to secretin, was ineffective. The maximal response of tyrosine hydroxylase activation to 1 microM secretin occurred within 6-15 sec. Secretin, VIP, and forskolin also enhanced tyrosine hydroxylase activity (3,4-dihydroxyphenylalanine production) in intact cells, as determined by high performance liquid chromatography and electrochemical detection. Secretin, VIP, PHI, and glucagon increased the levels of cAMP in PC12 cells more than 10-fold, as determined by radioimmunoassay. We also demonstrated that cAMP is released from the cells into the incubation medium following secretin treatment. Secretin and VIP treatment also enhanced the activity of cAMP-dependent protein kinase in a concentration-dependent fashion, as measured subsequently in vitro. Based on the greater potency of secretin in comparison with VIP, PHI, and glucagon, we suggest that the PC12 cells contain a secretin-preferring receptor that increases cAMP levels and brings about an activation of tyrosine hydroxylase activity through the stimulation of cAMP-dependent protein kinase.
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PMID:Regulation of tyrosine hydroxylase activity in rat PC12 cells by neuropeptides of the secretin family. 257 21

1. Vasoactive intestinal polypeptide (VIP) is present in high concentrations in the hypothalamus and appears to be involved in the modulation of growth hormone (GH) secretion. The effects of VIP on hypothalamic somatostatin (SMS) release are, however, controversial. 2. To further elucidate the mechanism of action of this peptide on GH secretion we studied the effects of VIP on SMS secretion from incubated rat hypothalamic fragments in vitro. 3. At 10(-6) M, VIP induced a significant increase in basal SMS release (P less than 0.01), whereas at 10(-10) M it had an inhibitory effect. 4. We suggest that the increase in GH after in vivo administration of VIP may be modulated, at least in part, by a direct effect of this peptide on SMS neurons, while the stimulatory effect of high doses of VIP on SMS release may represent a pharmacological interaction of this peptide with growth hormone releasing hormone, peptide histidine isoleucine, or glucagon receptors.
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PMID:Dose-dependent effects of vasoactive intestinal polypeptide on somatostatin release from hypothalamic fragments in vitro. 257 24

The octapeptide Lys-Arg-Asn-Lys-Asn-Asn-Ile-Ala (Arg4 in the human sequence) is the C-terminal part of porcine oxyntomodulin, an endogeneous peptide which is a potent inhibitor of stimulated acid secretion. This octapeptide exhibits the whole range of biological activities of the parent hormone. In the present work we report an 1H n.m.r. investigation of the conformational properties of the octapeptides of pig and human sequences in dimethylsulfoxide-d6 (DMSO) solution. The various resonances were assigned on the basis of two-dimensional COSY and NOESY experiments. Other experiments such as (i) temperature and concentration dependence of the amide proton chemical shifts, (ii) effects of ionic strength, (iii) comparison of the spectra with different analogues, were performed. We showed that in DMSO, the conformation of the octapeptide is directly related to the ionisation state of the C-terminus carboxyl group of alanine. In carboxylic state, the peptide adopts an extended conformation, while in the carboxylate state the four last residues (Asn-Asn-Ile-Ala) are involved in a type II beta-turn structure probably locked by a salt bridge between the carboxyl group of Ala8 and the epsilon ammonium group of Lys4 (or the guanidinium group of Arg4). These observations provide an insight into the possible conformational tendencies of this peptide in biological media.
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PMID:1H n.m.r. conformational studies on the C-terminal octapeptide of oxyntomodulin, a beta-turn locked by a salt bridge. 259 65

Helodermin is structurally similar to VIP (vasoactive intestinal peptide) and PHI (peptide histidine isoleucine). Since VIP and PHI both stimulate insulin and glucagon secretion, we investigated the effects of helodermin on insulin and glucagon secretion in the mouse, both in the basal state and during administration of glucose and the cholinergic agonist carbachol. After intravenous injection at dose levels between 0.5 and 8.0 nmol/kg, helodermin markedly enhanced basal plasma glucagon levels, for example at 8 nmol/kg from 139 +/- 14 to 421 +/- 86 pg/ml (p less than 0.001) after 6 minutes, without affecting basal plasma insulin levels. Together with glucose (2.8 mmol/kg), helodermin (2 and 8 nmol/kg) augmented plasma glucagon levels but had no effect on plasma insulin levels. When injected together with the cholinergic agonist carbachol (0.16 mumol/kg), helodermin markedly potentiated the increase in plasma glucagon levels (more than three-fold; p less than 0.001), again without affecting the plasma insulin levels. Combined alpha- and beta-adrenoceptor blockade (yohimbine + L-propranolol) reduced the augmenting effect of helodermin on glucagon secretion by approximately 60%. It is concluded helodermin stimulates glucagon secretion in the mouse by an effect that is partially antagonized by combined alpha- and beta-adrenoceptor antagonism.
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PMID:Helodermin stimulates glucagon secretion in the mouse. 267 15

Electrical stimulation of the preganglionic cervical sympathetic trunk causes an increase in dopa synthesis in the postganglionic neurons in the superior cervical ganglion (SCG). This transsynaptic biochemical effect can be blocked only partially by cholinergic antagonists, suggesting the involvement of a noncholinergic preganglionic sympathetic neurotransmitter(s). A survey of a large number of possible candidates for this neurotransmitter revealed that, in addition to cholinergic agonists, only a small group of peptides (all members of the secretin-glucagon family) stimulated dopa synthesis in the SCG. The effective peptides included vasoactive intestinal peptide (VIP), peptide histidine isoleucine amide (PHI), and secretin. Consequently we looked for the presence of immunoreactivities for these three peptides in the SCG. VIP- and PHI-like immunoreactive fibers were found in the SCG and in its major pre- and postganglionic nerve trunks. The distributions of the two immunoreactivities were very similar. Immunoreactive fibers were seen both singly and in bundles. In some instances, fibers were found apposed to neuronal cell bodies in the ganglion, and occasionally dense plexuses of fibers were found surrounding the neurons. In addition, punctate immunoreactive profiles were found apposed to the neurons in what appeared to be terminal fields. A small number of immunoreactive neuronal cell bodies were also seen in the ganglion. In a few instances, it was possible to establish, in serial sections, that the same cell body was immunostained with both VIP and PHI antisera. No secretin like-immunoreactive fibers or cells were observed. The presence of VIP-like and PHI-like-immunoreactive fibers in the cervical sympathetic trunk and in the SCG strengthens the possibility that these peptides, or a related molecule(s), serve as preganglionic neurotransmitters in this ganglion.
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PMID:Localization of vasoactive intestinal peptide- and peptide histidine isoleucine amide-like immunoreactivities in the rat superior cervical ganglion and its nerve trunks. 270 64

The effect of vasoactive intestinal peptide (VIP) and related peptides [glucagon, secretin, PHI 1-27 (peptide with N-terminal histidine and C-terminal isoleucine)] on renal adenylate cyclase (AC) has been determined in several species. The largest stimulation (4.1 +/- 0.5-fold basal) of AC by 1 mumol.l-1 VIP was observed in feline cortical plasma membranes. In rabbit and guinea-pig, VIP increased AC activity 1.5 +/- 0.3- and 1.8 +/- 0.3-fold respectively but glucagon had no such action. Conversely in the rat glucagon stimulated AC some 3-fold over basal activity whereas VIP had little effect. In dog, cat and mouse both peptides were effective in increasing AC activity. For cat, half-maximal stimulation of cortical plasma membrane AC by VIP was seen at 27.0 +/- 9.0 nmol.l-1 (SE N = 9 animals). VIP also increased AC activity in both outer (red) and inner (white) medulla. In feline cortical membranes VIP and PTH (parathyroid hormone) when added in combination were fully additive. However for VIP and glucagon in combination there was no cumulative increase in AC activity, indeed the resultant activity was less than that attained by VIP alone. The VIP analogue (4Cl-D-Phe6Leu17)VIP at 10 mumol.l-1 produced a right shift in the VIP-dose response curve and increased the EC50 from 17.2 +/- 5.8 nmol.l-1 to 132.0 +/- 22.2 nmol..-1 VIP (SE N = 4). There was no reduction in the maximum response elicited by VIP consistent with a competitive type of antagonism by this analogue. PHI-stimulated AC was also reduced by (4Cl-D-Phe6Leu17)VIP resulting in a similar right shift in the dose response curve.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vasoactive intestinal peptide stimulation of renal adenylate cyclase and antagonism by (4Cl-D-Phe6Leu17)VIP. 275 76

Antisera against peptide histidine isoleucine and peptide histidine methionine were found to label a subpopulation of amacrine and displaced amacrine cells in the rabbit retina with processes ramifying in sublaminas 1, 3 and 5 of the inner plexiform layer. Preadsorption controls demonstrated that this immunoreactivity was specific for a peptide histidine isoleucine- or peptide histidine methionine-like (peptide histidine isoleucine/peptide histidine methionine-like) peptide, and was not caused by cross-reactivity of the peptide histidine isoleucine or peptide histidine methionine antibodies with vasoactive intestinal peptide vasoactive intestinal peptide. In double-label studies, vasoactive intestinal peptide and peptide histidine isoleucine/peptide histidine methionine-like immunoreactivity were colocalized in the same population of retinal neurons. Electron microscopic analysis revealed that the peptide histidine isoleucine/peptide histidine methionine-labelled cells interacted with processes of bipolar cells, amacrine cells and ganglion cells. Peptide histidine methionine and peptide histidine isoleucine were slightly less potent than vasoactive intestinal peptide in stimulating adenylate cyclase activity in the rabbit retina, while the related peptides secretin, glucagon, and the C-terminal vasoactive intestinal peptide fragment, vasoactive intestinal peptide (10-28), showed little or no stimulatory activity. Stimulation of adenylate cyclase by high concentrations of vasoactive intestinal peptide and peptide histidine methionine were non-additive. These results suggest that a peptide histidine isoleucine/peptide histidine methionine-like peptide may function as a neuroactive peptide in the mammalian retina, and that this peptide appears to be cosynthesized and colocalized with vasoactive intestinal peptide and to mimic the activity of vasoactive intestinal peptide through interaction with vasoactive intestinal peptide receptor-adenylate cyclase complexes.
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PMID:A peptide histidine isoleucine/peptide histidine methionine-like peptide in the rabbit retina: colocalization with vasoactive intestinal peptide, synaptic relationships and activation of adenylate cyclase activity. 279 47

The ability of members of the secretin-glucagon family of peptides to modulate the responses of mouse lymphoid cells stimulated with Concanavalin A (Con A), Lipopolysaccharide (LPS) and alloantigens was determined. It was observed that vasoactive intestinal peptide (VIP) and peptide having NH2-terminal histidine and COOH-terminal Isoleucine (PHI) inhibited the incorporation of 3H-methyl-thymidine by cells stimulated with Con A (55% inhibition) or alloantigen-bearing cells (40% inhibition). Secretin was approximately 10,000 less effective as an immunomodulator. Other members of the neuropeptide family, including glucagon and gastric inhibitory peptide, were ineffective in affecting mitogenesis elicited by Con A (20% inhibition). Lipopolysaccharide stimulated spleen cells were refractory to modulation by all members of the secretin-glucagon family of peptides (less than 5% modulation). The inhibition measured was concentration dependent over the range of 10(-6) to 10(-16) M. A peptide fragment of VIP encompassing amino acid residues 10-28, although capable of modulating in vitro responses, was 30-50% less effective than intact VIP. In addition, a VIP specific binding assay for mouse lymphoid cells was described. The binding of 125I-VIP to lymph node cells was rapid, saturable and reversible. Apparent equilibrium was reached within 15 minutes and nonspecific binding, measured as 125I-VIP binding in the presence of an excess (2 x 10(-7) M) of native VIP, did not exceed 25% of the total binding. In competitive experiments using VIP related peptides, PHI but not gastric inhibitory peptide, glucagon or secretin was able to significantly inhibit 125I-VIP binding. PHI had only one-eighth of the competitive capacity of native VIP. Scatchard analyses indicated the existence of a single class of high affinity receptors on lymph node cells (KD = 3.46 nM; 26,000 sites/cell). 125I-VIP specific binding to purified T cells (14%) was markedly higher than to B cells (3% binding). Thymocytes bound less than 2% of the label and had relatively few VIP binding sites (8,000) as compared with purified T cells (45,000 sites/cell). There was variability in the ability of various T cells tumors and functional T cell clones to bind 125I-VIP. The role of VIP as a physiological modulator of T cell activation is discussed.
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PMID:Analysis of the immunomodulatory properties of the secretin-glucagon family of peptides on mouse lymphoid cell functions and the demonstration of specific receptors on T cells. 283 22

Specific binding sites for 125I-labelled rat peptide-histidine-isoleucine (PHI) were identified on rat insulinoma-derived RINm5F cells. The concentrations of peptides producing half-maximal displacement of label were rat PHI, 0.36 +/- 0.14 nM, vasoactive intestinal polypeptide (VIP), 0.38 +/- 0.13 nM and secretin, approximately 0.2 microM. Glucagon and glucagon-like peptide-1(7-36)amide were without effect on binding. PHI and VIP produced dose-dependent increases in cAMP production in the cells that were significantly (P less than 0.05) above unstimulated rates for ligand concentrations between 10(-8) and 10(-6) M. Both PHI and VIP produced a small but significant (P less than 0.05) enhancement in the rate of release of immunoreactive insulin from the cells but the effect was not dose dependent.
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PMID:Binding sites for peptide-histidine-isoleucine (PHI) on rat insulinoma-derived RINm5F cells. 285 Sep 58

The hypothalamic peptide vasoactive intestinal peptide (VIP) stimulates ACTH and endorphin secretion by the AtT20/D16 clonal strain of mouse pituitary tumor cells. The dose dependence for VIP stimulation of hormone release is biphasic, indicating that VIP is able to activate at least two classes of receptors in D16 cells (ED50 = 1.6 and 160 nM). We show that at high concentrations (ED50 greater than or equal to 150 nM), other natural peptides with primary structures homologous to that of VIP also increased ACTH secretion by D16 cells, whereas structurally unrelated peptides did not. The stimulatory actions of GH-releasing factor (GRF) and porcine heptacosapeptide with amino-terminal histidine and carboxy-terminal isoleucine amide (PHI) were mediated by high affinity VIP receptors because their effects were not additive with that of 10 nM VIP. In addition, GRF and PHI behaved as antagonists at low affinity VIP receptors; both peptides inhibited stimulation by 1 microM VIP. In contrast, glucagon and gastric inhibitory polypeptide appeared to stimulate ACTH release via low affinity VIP receptors because their effects were additive with that of 10 nM, but not 1 microM, VIP. Since all of the VIP-like peptides increased ACTH secretion only at high concentrations, they were unlikely to represent a physiological ligand for the receptor activated by high concentrations of VIP. Therefore, we determined whether cross-reactivity occurred between VIP-like peptides and corticotropin-releasing factor (CRF), a potent stimulator of ACTH secretion both in vitro and in vivo. The dose-response curve for CRF stimulation of ACTH secretion by D16 cells extended over more than a 1000-fold range of concentrations and was biphasic (ED50 = 2.6 and greater than 300 nM), indicating that CRF interacted with multiple receptor types in D16 cells. However, since the effect of 10 nM CRF was additive with that of 1 microM VIP, the CRF receptor was not the site at which high concentrations of VIP stimulated ACTH release. In contrast, the effect of 1 microM CRF was not additive with that of 1 microM VIP or other VIP-like peptides. Therefore, high concentrations of CRF and the previously recognized VIP-like peptides stimulated ACTH secretion by overlapping pathways. Comparison of the amino acid sequence of CRF with those of the VIP-like peptides showed that 18 of the 41 amino acids in CRF match a corresponding amino acid in at least 1 member of the VIP peptide family.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Peptide specificity for stimulation of corticotropin secretion: activation of overlapping pathways by the vasoactive intestinal peptide family and corticotropin-releasing factor. 285 86

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