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)

1. The primordial GRF may have arisen quite early in evolutionary history, at or prior to (i.e. should immunoreactivity data be confirmed in invertebrates) the appearance of jawed vertebrates (Gnathostomates). A common evolutionary pathway using gene duplication may have been utilized to generate the GRF super-family of peptides. As most members of this peptide superfamily are produced in the gastrointestinal tract, the question is posed whether the GRF may have similar origins. 2. It is suggested that the GRF superfamily has two major branches: a) GRF; PRP/PACAP; VIP/PHI; secretin and b) Glucagon/GLP-1/GLP-2. GIP is likely to be a member of the glucagon branch. The two branches may be attributable to gene duplication encoding an ancestral molecule. These gene duplications are likely to have occurred prior to the evolution of vertebrates (conservatively 400-500 million years ago, and possibly 1 billion years ago). It is probable that peptides homologous to GRF, VIP and glucagon will be isolated from invertebrates. These invertebrate sequences will shed further light upon the evolution of this peptide superfamily. 3. Throughout the GRF superfamily, amphiphilic alpha-helical secondary structures represent preferred bioactive conformations. It is assumed that stable, ordered secondary structures conferring enhanced ligand-receptor interactions were conserved due to selective pressures. 4. It is well documented that hypothalamic GRF stimulates adenohypophyseal GH secretion in a variety of species. Thus far, the physiological effects of GRF have been attributed thus to the elevation of GH, and possibly also IGF-I. Recent data suggests a more liberal view; that GRF may also have direct actions in fetal/placental development, reproduction and immune function. Furthermore these direct effects may be mediated via GRF from either hypothalamic or extrahypothalamic (e.g. placenta, testes, ovary, leukocyte) sources. In conclusion, a great wealth of information has accumulated since the discovery of GRF. Examination of the GRF peptide superfamily from an evolutionary perspective has revealed new insights into the synthesis, processing, degradation, conformation and activities of these molecules. Knowledge obtained from these evolutionary comparisons has also become particularly useful in contemporary peptide drug design, which may be liberally viewed as a form of 'artificial evolution' (i.e. the selective pressure being clinical/veterinary requirements for more potent, long-acting GRF analogs).
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PMID:Evolution of the growth hormone-releasing factor (GRF) family of peptides. 129 Sep 54

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 high and low affinity binding sites for PACAP were identified in rat astrocytes using [125I]PACAP27 as the labeled ligand. Scatchard analysis of displacement of the bound tracer by unlabeled PACAP27 indicated the existence of two classes of binding sites, with the dissociation constant (Kd) = 1.22 +/- 0.4 nM, the binding maximal capacity (Bmax) = 821 +/- 218 fmols/mg protein for the high affinity binding site, and Kd = 0.59 +/- 0.06 microM, Bmax = 563 +/- 12 pmols/mg protein for the low affinity binding site, respectively. The specificity of [125I]PACAP27 binding was tested using PACAP38 and peptides structurally related to PACAP, such as VIP, GHRF, PHI, secretin and glucagon. PACAP38 completely displaced the binding of [125I]PACAP27 and Scatchard analysis also indicated the presence of two classes of binding sites with similar Kd and Bmax to those for PACAP27. VIP and GHRF competed with [125I]PACAP27, but to a much lesser extent than unlabeled PACAP27 in binding. Other peptides tested did not displace the binding of [125I]PACAP27 at 10(-6) M.
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PMID:Demonstration of specific binding sites for pituitary adenylate cyclase activating polypeptide (PACAP) in rat astrocytes. 234 75

Two types of cDNA encoding PACAP receptors were isolated from the rat brain cDNA library by homology screening with a cDNA probe for VIP receptor. Nucleotide sequence analysis indicated that these two types of receptor mRNA were generated by alternative splicing mechanisms. These two cloned cDNAs were introduced into CHO cells respectively. Resultant transformants showed specific binding to [125I]PACAP27 which was displaced by unlabeled PACAP27 but not by VIP. Thus, these receptors are two subtypes of Type I PACAP receptor (Type I-A and Type I-B). The amino acid sequences of rat PACAP receptors deduced by the cDNAs showed a remarkable similarity with rat receptors for VIP, secretin, glucagon, and GHRH. A 6.5 kb significant hybridizing signal of the PACAP receptor mRNA was detected in the rat brain, and slight signal was also detected in the lung and the liver.
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PMID:Molecular cloning and functional expression of rat cDNAs encoding the receptor for pituitary adenylate cyclase activating polypeptide (PACAP). 768 25

The effects of PACAP on hepatic glucose metabolism were examined using the flow-through perfusion method for fed rat livers, because some of the glucagon superfamily peptides stimulate hepatic glucose output. Glucose output was significantly stimulated in a dose-dependent manner by more than 1 nM PACAP-27. The potency of its stimulation was equal to that of PACAP-38, greater than that of VIP, and clearly lower than that of glucagon. The cAMP output was also increased significantly by more than 1 nM PACAP-27; however, the degree and profile of cAMP output were not in parallel with those of glucose. Theophylline did not affect these stimulatory effects. On the other hand, in the perfusion experiment with Ca2+ free perfusate, the degrees of increase in glucose output induced by 15 and 40 nM PACAP-27 were significantly reduced. In conclusion, PACAP stimulates glucose output from the perfused rat liver, and Ca2+ rather than cAMP plays an important role in this action as a second messenger.
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PMID:PACAP stimulates glucose output from the perfused rat liver. 771 74

Pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) is a neuropeptide related to vasoactive intestinal peptide-secretin-glucagon which stimulates adenylate cyclase in cultured rat pituitary cells and stimulates LH and FSH release in vitro and in vivo. Because the cAMP-protein kinase-A pathway regulates the gonadotropin subunit messenger RNAs (mRNAs) and modulates GnRH-stimulated gonadotropin secretion in vitro, we examined the effects of PACAP38 on gonadotropin secretion and subunit mRNA levels. Anterior pituitary cells were prepared from 7-week-old male rats castrated at 5 weeks of age. In monolayer cultures stimulated with GnRH, 0.1-10 nM PACAP38 decreased (P < 0.05) the EC50 for GnRH dose-dependently without affecting the maximum LH secretory response. Cells were next stimulated with 1-min pulses of 2.5 nM GnRH every hour for 9 h in the absence or presence of 10 nM PACAP38, which was perifused continuously. The amplitude of GnRH-induced LH, FSH, and alpha-subunit secretory episodes from PACAP38-treated cells rose (P < 0.01) gradually to 233 +/- 54%, 197 +/- 44%, and 378 +/- 104%, respectively (mean +/- SEM; n = 5 experiments), of the value for control cells lacking PACAP38. This enhancement was sustained for at least 3 h after PACAP38 was removed from the perifusion medium. With PACAP treatment, interpulse secretion of LH and alpha-subunit increased gradually (P < 0.01) to 174 +/- 21% and 212 +/- 64% of the value for chambers stimulated with GnRH alone (control), respectively, whereas interpulse secretion of FSH declined (P < 0.001) to 75 +/- 7% of the control value. In contrast to the gradual effect of PACAP38 to enhance GnRH-induced hormone secretion, PACAP38 alone produced a transient burst of gonadotropin secretion. At the completion of the perifusions, total RNA was extracted and gonadotropin subunit mRNA levels were determined by Northern analysis. GnRH increased (P < 0.01) FSH beta mRNA to 438 +/- 52% of the level in cells stimulated with medium alone (control). Adding PACAP38 to the perifusion medium partially blocked (P < 0.01) the effect of GnRH (178 +/- 20% of the control value), and PACAP38 alone reduced (P < 0.01) FSH beta mRNA levels to 31 +/- 3% of the control value. By contrast, alpha-subunit mRNA levels were increased by both PACAP38 (143 +/- 4% of the control value; P < 0.01) and GnRH (121 +/- 2% of the control value; P < 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of pituitary adenylate cyclase-activating polypeptide on gonadotropin secretion and subunit messenger ribonucleic acids in perifused rat pituitary cells. 791 30

When pituitary adenylate cyclase activating polypeptide (PACAP-38, 420 pmol/kg) was injected to anesthetized dogs, hyperglycemia associated with elevation in plasma glucagon and adrenalin levels was observed. In dogs undergone adrenalectomy, the same dose of it stimulated insulin, but not glucagon, release and hyperglycemia was not observed. Much higher dose was needed to evoke hyperglycemia in such dogs. Next, direct glycogenolytic activities of PACAP, glucagon and adrenalin were studied on cultured rat hepatocytes. PACAP38 stimulated glucose output via cAMP production by the cells, but the potency was far less than that of glucagon. Adrenalin, however, could not exert the activity with physiological concentrations. These results indicate that hyperglycemic effect of PACAP can be attributed mainly to indirect effects resulting from glucagon and adrenalin release and possibly in part to a direct action on hepatocytes.
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PMID:Glycogenolytic activity of pituitary adenylate cyclase activating polypeptide (PACAP) in vivo and in vitro. 793 19

The binding of ovine pituitary adenylate cyclase-activating peptide (PACAP-38) to rat lung membranes was investigated using [125I]PACAP-38 as radioligand. Binding was rapid at 37 degrees C, reversible, saturable, and time, concentration, and temperature dependent. Kinetic parameters derived from saturation experiments revealed a Kd = 100 +/- 15 pM, Bmax = 310 +/- 36 fmol/mg protein, and a Hill slope factor (nH) of 1.17 +/- 0.12. Various chemically synthesized analogues of PACAP-38, as well as related peptides, were tested for their ability to displace [125I]PACAP-38. Of those that had an IC50 < 0.2 microM, the following order of potency was determined: PACAP-38 (IC50 = 25 nM) > or = [Ile2]PACAP-38 (IC50 = 31 nM) > PACAP-27 (IC50 = 54 nM) > [Tyr1]PACAP-38 (IC50 = 104 nM) > GHRH(1-29)NH2 (IC50 = 108 nM) > PHI (IC50 = 181 nM) > [Ser2]PACAP(2-38) (IC50 = 198 nM). Glucagon, PHM, secretin, and GIP exhibited little affinity in the same binding assay. Vasoactive intestinal peptide (VIP) had an IC50 in excess of 1 microM. When [125I]VIP was used as radioligand, PACAP-27 had an IC50 = 0.2 nM > PACAP-38 (IC50 = 0.5 nM) > VIP (IC50 = 16 nM). A novel analog of PACAP-38, [4-Cl-D-Phe6,Leu17]PACAP-38, was able to displace [125I]VIP very efficiently (IC50 = 1 nM), but had little potency in displacing [125I]PACAP-38 (IC50 = 320 nM).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interaction of ovine pituitary adenylate cyclase-activating peptide (PACAP-38) with rat lung membranes. 839 24

Pituitary adenylate cyclase-activating polypeptide (PA-CAP) is a polypeptide hormone related to vasoactive intestinal polypeptide (VIP). Rat PACAP receptor cDNA was isolated from a brain cDNA library by cross-hybridization with rat VIP receptor cDNA. The recombinant PACAP receptor expressed in COS cells bound PACAP with about 1000 times higher affinity than VIP, and PACAP stimulated adenylate cyclase through the cloned PACAP receptor. The rat PACAP receptor consists of 495 amino acids, contains seven transmembrane segments, and has a significant similarity with other Gs-coupled receptors, such as VIP, glucagon, and secretin receptors. PACAP receptor mRNA was abundantly expressed in the brain, but not in the peripheral tissues except for the adrenal gland. In situ hybridization revealed a high level of expression of PACAP receptor mRNA in the hippocampal dentate gyrus, olfactory bulb, and cerebellar cortex.
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PMID:Molecular cloning and tissue distribution of a receptor for pituitary adenylate cyclase-activating polypeptide. 839 23

The two forms of pituitary adenylyl cyclase-activating polypeptide (PACAP-27 and -38) are neuropeptides of the secretin/glucagon/vasoactive intestinal polypeptide/growth-hormone-releasing hormone family and regulate hormone release from the pituitary and adrenal gland. They may also be involved in spermatogenesis, and PACAP-38 potently stimulates neuritogenesis and survival of cultured rat sympathetic neuroblast and promotes neurite outgrowth of PC-12 cells. The PACAP type-I receptor (found in hypothalamus, brain stem, pituitary, adrenal gland and testes), specific for PACAP, is positively coupled to adenylyl cyclase and phospholipase C. The recently cloned type II receptor does not discriminate between PACAP and vasoactive intestinal polypeptide and is coupled to only adenylyl cyclase. Here we have used a new expression cloning strategy, based on the induction of a reporter gene by cyclic AMP, to isolate a complementary DNA encoding the type-I PACAP receptor. On transfection of this cDNA, both PACAP-27 and -38 stimulate adenylyl cyclase with similar EC50 values (50% effective concentration, 0.1-0.4 nM), whereas only PACAP-38 stimulates phospholipase C with high potency (EC50 = 15 nM). Four other splice variants were isolated with insertions at the C-terminal end of the third intracellular loop. Expression of these cDNAs revealed altered patterns of adenylyl cyclase and phospholipase C stimulation, suggesting a novel mechanism for fine tuning of signal transduction.
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PMID:Differential signal transduction by five splice variants of the PACAP receptor. 839 27


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