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)

The solution structures of the recently discovered neuropeptides PACAP38 and PACAP27 have been investigated in aqueous solution containing varying amounts of trifluoroethanol (TFE) by circular dichroism (CD) spectroscopy and a combination of 2D 1H nuclear magnetic resonance (NMR) spectroscopy, distance geometry, and refined molecular dynamics and energy minimization calculations. In aqueous solution both peptides show only small transitory amounts of stable structure while in 50% TFE they adopt ordered structures. Qualitative NOE data and the use of the chemical shift index of the alpha-protons identified the positions of alpha-helical regions. A set of low-energy conformations compatible with the quantitative NOE data were obtained for both and each set were subjected to RMS analysis to determine the positions of the secondary structure elements. PACAP38 has an initial disordered N-terminal domain of eight amino acids, followed by an alpha-helical structure stretching from Ser-9 to Val-26, which contains a discontinuity between Lys-20 and Lys-21, and in the C-terminal region there is a short alpha-helix between Gly-28 and Arg-34. The structure of PACAP27 mirrors remarkably closely that of PACAP38 and shows no fraying of the C-terminal helix. The physiological significance of the three structural domains (1-8, 9-26, and 27-38) of PACAP38 is shown by a comprehensive review of recent in vitro and in vivo investigations of PACAP analogues. The correspondence of the global structural features of PACAP with other members of this family of peptides (namely, secretin, glucagon, GHRF1-29 and VIP) is demonstrated by inspection of the chemical shift indices of the alpha-protons.
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PMID:Solution structure of pituitary adenylate cyclase activating polypeptide by nuclear magnetic resonance spectroscopy. 850 3

During migration and for about 2 days after their arrival in the gonadal ridges, primordial germ cells (the embryonic precursors of gametes of the adult animal) proliferate actively. Certain growth factors, such as stem cell factor and leukemia inhibitory factor, seem to be essential for survival, proliferation and possibly differentiation of mouse primordial germ cell in vivo and/or in vitro. Similarly, increase in intracellular cAMP is followed by a marked enhancement of primordial germ cell proliferation, at least in culture. In the present study, we show that pituitary adenylate cyclase-activating polypeptides (PACAP-27 and PACAP-38), two neuropeptides of the secretin-glucagon-vasoactive intestinal polypeptide-GH-releasing hormone family, stimulate in vitro proliferation of mouse primordial germ cells, bind to primordial germ cells and gonadal somatic cells (possibly to type I PACAP receptor) and activate adenylate cyclase in the same cells. Moreover, PACAP-like immunoreactivity was found in gonadal ridges, mostly on germ cell surface. In conclusion, evidence is provided that PGC proliferation can be stimulated by certain bioactive polypeptides, thus suggesting a novel regulatory role for such compounds in early gonad development.
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PMID:Pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates adenylate cyclase and promotes proliferation of mouse primordial germ cells. 856 32

The two forms of pituitary adenylate cyclase-activating polypeptide, PACAP27 and PACAP38, are two neuropeptide hormones related to the vasoactive intestinal peptide/secretin/ glucagon family of peptides. PACAP receptors that are positively coupled to adenylyl cyclase and phospholipase C have been identified in cultured cerebellar granule cells. Using the reverse transcription-polymerase chain reaction methodology, we demonstrated the expression of the PACAP-R and PACAP-R-hop mRNAs in cultured granule cells. When grown in the absence of serum or in low K+ concentrations, these neurons underwent apoptosis, a naturally occurring process characterized by cell shrinkage and internucleosomal DNA cleavage. We used these models of programmed cell death to study the relationship between PACAP receptor activation and neuronal apoptosis. Treatment with PACAP27 and PACAP38 reduced the development of apoptosis in a dose-dependent manner. The neuroprotective activity of PACAP was mimicked by high concentrations of vasoactive intestinal peptide or forskolin but not by carbamylcholine. Thus, we suggest that the activation of type I PACAP receptors may contribute to the survival of cerebellar granule neurons.
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PMID:Pituitary adenylate cyclase activating polypeptide prevents apoptosis in cultured cerebellar granule neurons. 870 Jan 20

The two forms of pituitary adenylate cyclase-activating polypeptide, PACAP27,and PACAP38, are novel members of the vasoactive intestinal peptide (VIP)/secretin/glucagon family of peptides. PACAP receptors that are positively coupled to adenylate cyclase and phospholipase C have been recently identified. We examined the expression of PACAP receptors in the rat cortex, hippocampus, cerebellum and hypothalamus during postnatal development. Functional studies revealed PACAP stimulation of cAMP formation in all the brain areas examined and [3H]inositol monophosphate ([3H]InsP) accumulation only in the cerebellum and hypothalamus. Throughout development, the efficacy or PACAP in stimulating cAMP formation slightly increased in the cortex and hypothalamus and decreased in the hippocampus and cerebellum; PACAP stimulation of [3H]InsP formation decreased in the cerebellum and remained steady in the hypothalamus. The effects of PACAP27 and PACAP38 on cAMP levels and inositol phospholipid hydrolysis were dose-dependent between 1 and 100 nM. In the same brain areas, treatment with VIP increased cAMP formation at doses greater than 100nM and failed to affect [3H]InsP content, thus suggesting the existence of type-1 PACAP receptors. The reverse transcription polymerase chain reaction (RT-PCR) was used to analyse the mRNA expression of type-1 PACAP receptor splice variants. PACAP receptor gene expression in the central nervous system was regulated in a developmental- and tissue-specific manner. The PACAP-R transcript was detected in all the brain areas examined whereas PACAP-R-hop mRNA ocurred only in the cerebellum and hypothalamus. The different expression profiles and functional properties of PACAP receptors in the developing rat brain suggest an involvement of PACAP in histogenesis, maturation and neurotransmission.
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PMID:Tissue-specific and developmental expression of pituitary adenylate cyclase-activating polypeptide (PACAP) receptors in rat brain. 871 2

Pituitary adenylate cyclase-activating polypeptides (PACAP-27 and PACAP-38) are neuropeptides of the vasoactive intestinal polypeptide (VIP)/secretin/glucagon family. PACAP receptors are expressed in different brain regions, including cerebellum. We used primary culture of rat cerebellar granule neurons to study the effect of PACAP-38 on apoptosis induced by potassium deprivation. We demonstrated that PACAP-38 increased survival of cerebellar neurons in a dose-dependent manner by decreasing the extent of apoptosis estimated by DNA fragmentation. PACAP-38 induced activation of the extracellular signal-regulated kinase (ERK)-type of mitogen-activated protein (MAP) kinase through a cAMP-dependent pathway. PD98059, an inhibitor of MEK (MAP kinase kinase), completely abolished the antiapoptotic effect of PACAP-38, suggesting that MAP kinase pathway activation is necessary for PACAP-38 action.
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PMID:Pituitary adenylate cyclase-activating polypeptide (PACAP-38) protects cerebellar granule neurons from apoptosis by activating the mitogen-activated protein kinase (MAP kinase) pathway. 898 38

PACAP and GLP-1 depolarize pancreatic beta cells and stimulate insulin secretion in the presence of glucose. Depolarization occurs through at least two distinct mechanisms: (1) closure of ATP-sensitive K+ channels, and (2) activation of nonselective cation channels (NSCCs). Under physiological conditions the NSCCs carry a predominantly Na(+)-dependent current. The current may also have a Ca2+ component, but this remains to be determined. Acting together, these two signaling systems reinforce each other and serve to promote membrane depolarization, a rise of [Ca2+]i, and exocytosis of insulin-containing secretory granules. The NSCCs in beta cells are dually regulated by intracellular cAMP and [Ca2+]i. In view of this dual regulation, it appears likely that NSCC channel activation results from signaling events occurring not only at the plasma membrane (gating of channels by cAMP; protein kinase A-mediated phosphorylation of channels) but also at intracellular sites (mobilization of calcium stores by an as yet to be determined process). It is noteworthy that activation of NSCCs has also been reported following stimulation of beta-cells with maitotoxin, or after depletion of intracellular Ca2+ stores. Therefore, the possibility arises that PACAP, GLP-1, and maitotoxin all act on the same types of ion channels in these cells, and that these channels are sensitive to alterations in the content of intracellular calcium. FIGURE 6 summarizes our current knowledge concerning the properties of the PACAP and GLP-1 signaling systems as they pertain to the regulation of NSCCs and intracellular calcium homeostasis in the beta cell. Given that PACAP and GLP-1 are proven to be exceptionally potent insulin secretagogues, it is of considerable interest to determine their usefulness as blood glucose-lowering agents. Initial evaluations of the therapeutic effectiveness of GLP-1 indicate a role for this peptide in the treatment of NIDDM, and also possibly insulin-dependent diabetes mellitus (IDDM). A very attractive feature of such a strategy is the demonstrated lack of hypoglycemic side effects attendant to administration of GLP-1 to diabetic subjects. These observations reinforce the notion that peptides of the PACAP/glucagon/VIP family represent important pharmacological tools for use in experimental therapeutics.
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PMID:Signal transduction of PACAP and GLP-1 in pancreatic beta cells. 899 95

PACAP is a member of the secretin/glucagon/VIP family of peptides and demonstrates neurotrophic and neuroprotective effects at very low concentrations. We have previously shown that PACAP crosses the BBB to a modest degree by way of a saturable transport system. PACAP is transported across the BBB as an intact peptide to enter the parenchymal space of the brain. We tested the possibility that this modest rate of transport would be sufficient to produce the low levels of PACAP needed in the brain to exert a neuroprotective effect against ischemia. We found that PACAP given intravenously could indeed prevent the death of CA1 hippocampal neurons, even if the administration of PACAP was delayed for 24 h after the ischemic event. We suggest that iv PACAP could be neuroprotective after stroke, cardiac arrest, and hypotensive episodes.
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PMID:Transport of pituitary adenylate cyclase-activating polypeptide across the blood-brain barrier and the prevention of ischemia-induced death of hippocampal neurons. 899 9

PACAP-27 and PACAP-38 as low as 10(-13) M stimulate insulin release from rat islets in a glucose-dependent manner. PACAP also glucose dependently increases cAMP and [Ca2+]i in rat islet beta cells. The [Ca2+]i and insulin secretory responses to PACAP exhibit a similar concentration-response relationship, exhibiting a peak at 10(-13) M. When the [Ca2+]i response is abolished by nitrendipine, a blocker of L-type Ca2+ channels, the insulin response is also inhibited. Insulinotropic peptides glucagon, GLP-1, and VIP also increase [Ca2+]i in beta cells, but only in the nanomolar concentration range. PACAP is 4 logs more potent that VIP, a peptide that exhibits 68% amino acid homology and shares the type II PACAP receptor with PACAP. Immunoreactivity for the type I PACAP receptor is demonstrated in rat islets. Furthermore, PACAP immunoreactivity is demonstrated in nerve fibers and islets in rat pancreas. Based on these findings, we can draw the following conclusions: (1) PACAP is localized in pancreatic nerve fibers and islets; (2) PACAP in the subpicomolar range stimulates insulin release from islets; (3) the stimulation of insulin release is mediated by the cAMP-dependent increase in [Ca2+]i in beta cells; (4) all the PACAP effects are glucose-dependent; (5) PACAP is the most potent insulinotropic hormone known, and (6) the type I PACAP receptor appears to mediate the action of PACAP in the subpicomolar range. Finally, we hypothesize that PACAP is a pancreatic peptide of both neural and islet origin and functions as an intrinsic potentiator of glucose-induced insulin secretion in pancreatic islets (FIG 6).
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PMID:Current status of PACAP as a regulator of insulin secretion in pancreatic islets. 899 14

Vasoactive intestinal polypeptide (VIP) is a neuropeptide that has numerous physiological actions and is widely distributed in the body. However, as yet, there is no sequence information about VIP receptors in lower vertebrates. Partial cDNA fragments spanning transmembrane domains 2 to 6 of VIP receptors were isolated from six nonmammalian vertebrate species, including chicken, pigeon, frog, lizard, salmon, and goldfish. Sequence comparison of these receptors revealed essential structural motifs responsible for receptor function. In addition, the first nonmammalian full-length VIP receptor cDNA was obtained by screening a goldfish brain and pituitary cDNA library. Functional expression of this receptor in mammalian COS-7 cells showed that it is coupled to cAMP production in a VIP and PACAP concentration-dependent manner; the EC50 of VIP was determined to be 1 nM. At 100 nM peptide, the relative potency of various peptides in stimulating cAMP in the transfected cells was VIP > PACAP > GHRH = secretin > PHM > PTH > glucagon > GLP-1 > GIP. Characterization of the VIP receptors in lower vertebrates should enhance our understanding of the molecular evolution and physiology of VIP in vertebrates.
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PMID:Molecular evolution of vertebrate VIP receptors and functional characterization of a VIP receptor from goldfish Carassius auratus. 903 50

The pituitary adenylyl cyclase-activating polypeptide PACAP-(1-38) has potent pancreatic secretory effects. We studied its immunohistochemical localization, release, and contribution to secretion induced by electrical vagus stimulation using isolated perfused porcine pancreas and the PACAP receptor antagonist PACAP-(6-38) (10(-7) M). PACAP was found in nerve fibers throughout the pancreas but, in particular, encircling ganglionic vasoactive intestinal polypeptide (VIP)-positive nerve cell bodies and, mostly, colocalized with VIP. Vagus stimulation caused its release. PACAP-(1-38)(4 x 10(-9) M) stimulated exocrine and endocrine secretion and released VIP. PACAP-(6-38) decreased PACAP-induced flow of juice to 59 +/- 7.8% and insulin secretion and VIP release to 12 +/- 6.8 and 57 +/- 13%, respectively. Glucagon secretion was unaffected. PACAP-(6-38) reduced vagus-stimulated flow rate to 63 +/- 7.6%, insulin and glucagon responses to 31.8 +/- 13 and 6 +/- 4%, respectively, and VIP release to 23 +/- 8.4% and reduced VIP-induced (2 x 10(-9) M) juice and insulin (but not glucagon) outputs to 8.3 +/- 4.2 and 67 +/- 14%, respectively. In conclusion, 1) pancreatic PACAP fibers seem to activate intrapancreatic VIPergic neurons, 2) PACAP-(6-38) antagonism documents the role of VIP/PACAP for neural regulation but cannot distinguish their relative importance, and 3) a PACAP receptor with low affinity for PACAP-(6-38), associated with glucagon cells, may exist.
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PMID:PACAP-(1-38) as neurotransmitter in pig pancreas: receptor activation revealed by the antagonist PACAP-(6-38). 927 23


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