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

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide belonging to the vasoactive intestinal polypeptide (VIP)/glucagon/secretin family. We have isolated a third PACAP receptor subtype, designated PACAPR-3, by molecular cloning. The cDNA encoding PACAPR-3 has been isolated from a mouse insulin-secreting beta-cell line MIN6 cDNA library. Mouse PACAPR-3 is a protein of 437 amino acids that has 50% and 51% identity with rat PACAP type I and type II receptors, respectively. We have expressed PACAPR-3 in mammalian cells and Xenopus oocytes. PACAPR-3 binds to VIP as well as PACAP-38 and -27, with a slightly higher affinity for PACAP-38, and is positively coupled to adenylate cyclase. PACAP-38, -27, and VIP evoked Ca2+ activated-Cl- currents in Xenopus oocytes. RNA blotting studies reveal that PACAPR-3 mRNA is expressed widely in tissues and cell lines, including pancreatic islets, insulin-secreting cell lines (MIN6, HIT-T15, and RINm5F), lung, brain, stomach, colon, and heart. Furthermore, insulin secretion from the MIN6 cells is stimulated significantly by PACAP-38 and VIP. The possible mechanisms of insulin secretion by PACAP and VIP are also discussed.
 ...
PMID:PACAP/VIP receptors in pancreatic beta-cells: their roles in insulin secretion. 899 92

Pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide belonging to the VIP/secretin/glucagon family, is present in the hypothalamus, anterior pituitary, and adrenal gland where it regulates hormone release, in the GI tract where it modulates motility, and in human tumoral cell lines where it shows a growth-promoting effect. It is now appreciated that alternative splicing of two exons of the rat PACAP-R gene generate four major rPACAP-R splice variants that are differentially expressed in tissues and variably coupled to intracellular second messengers. Because of the potential implications of these findings in human physiology, we cloned the hPACAP-R gene. Similar to the rat, two exons (SV-1 and SV-2) are alternatively spliced to account for four major hPACAP-R receptor splice variants. These splice variants (hPACAP-R-null, hPACAP-R-SV1, hPACAP-R-SV2, hPACAP-R-SV-3) were cloned from a human frontal cortex cDNA library, stably transfected in NIH/ 3T3 cells and each characterized for ligand affinity, stimulation of adenylate cyclase (AC) and phospholipase C (PLC), and ligand-induced expression of the proto-oncogenes, c-fos, and c-myc. Stably transfected NIH/3T3 cells expressing similar numbers of receptors of the four splice variants showed nearly identical responses for ligand affinity and potency for P-38- and P-27-stimulated increases in cAMP and total inositol phosphates. However, each receptor splice variant differed in their ligand-stimulated efficacy for total inositol phosphate stimulation. The hPACAP-R-SV2 showed the greatest efficacy for stimulating phospholipase C that was approximately seven-fold greater than the hPACAP-R-SV1, twofold greater than the hPACAP-R-Null, and 1.5-fold greater than the hPACAP-R-SV-3 splice variants. To determine whether the splice variants also differ in their ability to stimulate immediate early gene expression, c-fos and c-myc transcripts were assayed by Northern blot and quantified by densitometry. PACAP-38 increased c-fos and c-myc expression for all four of the receptor splice variants that paralleled the efficacy for PLC stimulation, with the the SV-2 splice variant showing the greatest stimulation. These results show that the hPACAP-R-SV2 exhibits enhanced efficacy for coupling to both PLC and activation of the protooncogenes, c-fos and c-myc suggesting a novel and potentially important mechanism for differentially activating signal transduction pathways that influence cellular growth and differentiation.
 ...
PMID:Differential signaling and immediate-early gene activation by four splice variants of the human pituitary adenylate cyclase-activating polypeptide receptor (hPACAP-R). 899 93

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).
 ...
PMID:Current status of PACAP as a regulator of insulin secretion in pancreatic islets. 899 14

Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP), members of the glucagon-secretin family, have recently been suggested to be involved in the regulation of corticotropin (ACTH) secretion. In this study, we examined the effects of both peptides on POMC gene expression. Using AtT20PL, a clone of the AtT20 mouse corticotroph tumor cells stably transfected with 0.7 kb of the rat POMC 5' promoter-luciferase fusion gene, the effects of both peptides on the POMC promoter activity were estimated by a luciferase assay. PACAP stimulated POMC 5' promoter activity as well as cAMP generation and ACTH secretion in a dose- and time-dependent manner, with the maximal effect being observed 3 h after the start of incubation. A similar effect was observed with VIP. Although the combined effects of PACAP/CRH or VIP/CRH were greater than that of either hormone alone, no such effect was observed between PACAP and VIP. Furthermore, RT-PCR analysis showed the presence of only the PVR3 receptor subtype in this cell line, which is known to have a similar affinity to PACAP and VIP, indicating that both peptides exert their effects through the same receptor. In contrast to the effect of CRH, which was completely abolished by a protein kinase A inhibitor H89, the effects of PACAP/VIP on POMC expression persisted during H89 treatment, suggesting the involvement of alternative intracellular signaling pathway(s) distinct from the protein kinase A system. Our results suggest that PACAP and VIP have positive effects on POMC gene expression and that multiple signaling pathways are involved in the transcriptional event.
 ...
PMID:Regulation of the rat proopiomelanocortin gene expression in AtT-20 cells. II: Effects of the pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal polypeptide. 911 89

The vasoactive intestinal peptide/pituitary adenylate cyclase-activating polypeptide (PACAP)/secretin/glucagon family of peptides displays numerous physiological roles in autonomic nervous system development and function. The regulated endogenous production and release of PACAP peptides in sympathetic neurons of the superior cervical ganglion (SCG) was investigated. The two posttranslationally processed forms of PACAP, PACAP27 and PACAP38, were identified in rat adult, neonatal, and cultured SCG neurons. PACAP38 levels were approximately 5-10 fmol/adult SCG and approximately 2 fmol/neonatal SCG; PACAP27 levels were comparable. The authenticity of peptide immunoreactivity in these tissues was verified by coelution with synthetic PACAP in reverse-phase HPLC analysis. Reverse transcription-PCR and sequence-specific hybridization revealed PACAP mRNA in adult, neonatal, and cultured SCG neurons; in situ hybridization histochemistry and immunocytochemistry localized the PACAP peptide and proPACAP mRNA to a subset of the SCG neuronal population. Basal and stimulated release of endogenous PACAP38 from cultured sympathetic neurons was established, suggesting that these peptides may function as signaling molecules at target tissues. Chronic depolarization with 40 mM potassium stimulated the PACAP secretory rate 10- to 20-fold, with concomitant increases in cellular PACAP peptide and mRNA levels. When examined using Northern analysis, depolarizing conditions not only stimulated the 2.2 kb form of PACAP mRNA, but also induced the expression of a shortened, 0.9 kb, transcript. Further reverse-transcription PCR analysis demonstrated that this smaller transcript was not identical to the unique testicular message. These studies identify PACAP38 and PACAP27 as regulated endogenous releasable peptides contributing to the functional diversity and phenotypic plasticity of the sympathetic nervous system.
 ...
PMID:Identification of endogenous sympathetic neuron pituitary adenylate cyclase-activating polypeptide (PACAP): depolarization regulates production and secretion through induction of multiple propeptide transcripts. 915 21

To address the origin of the glucagon superfamily, we isolated and sequenced the complementary DNA and partial gene that encode pituitary adenylate cyclase-activating polypeptide (PACAP) from a protochordate (tunicate), a sister group of the amphioxus and vertebrates, but one that evolved before the amphioxus. This is the first report of any superfamily member sequenced from an invertebrate. Transcription of the tunicate pacap1 gene results in a messenger RNA that is 507 bp. The gene contains 3 exons that encode a signal peptide, GRF-like peptide(1-27), and PACAP(1-27). The tunicate GRF-like peptide has 59% identity with human GRF, whereas the deduced amino acids of tunicate PACAP(1-27) have 96% identity with the ovine, human, and salmon PACAP(1-27) forms. Another complementary DNA clone pacap2 was isolated and shown to contain 4 exons that encode a signal peptide, a cryptic peptide, and two peptides that are clearly members of the glucagon superfamily. One of the peptides has 89% sequence identity to the tunicate PACAP encoded in pacap1. A comparison of the two structurally related PACAP clones, each encoding two peptides on separate exons, shows high inter- and intraexon nucleotide sequence identity. Sequence analysis suggests that an exon duplication followed by a gene duplication was responsible for the origin of the two genes. It is argued that the PACAP gene is derived from the protochordate ancestral genes that led to the vertebrate forms of GRF and PACAP.
 ...
PMID:Two protochordate genes encode pituitary adenylate cyclase-activating polypeptide and related family members. 916 26

Pituitary adenylate cyclase activating polypeptide (PACAP), a member of the vasoactive intestinal polypeptide (VIP)/secretin/glucagon family, is known to be a powerful stimulator of adenylate cyclase. Recently, PACAP has been shown to stimulate cAMP in osteoblast-like cells and mouse calvarian bones. In the present study, PACAP immunoreactivity (IR) was demonstrated in cartilage canals from newborn and 3-4-week-old pigs. In tissues from the femoral head and the patella with and without ossification centres, PACAP-IR nerve fibres were found in the cartilage canals innervating blood vessels. The pattern of distribution was not dependent on age or the occurrence of an ossification centre. Co-localization studies showed a high degree of co-localization with calcitonin gene-related peptide (CGRP) and substance P (SP) but little co-localization with VIP. Our findings support earlier findings of CGRP, SP and VIP in bone tissue and add PACAP to the group of neuropeptides with a sensory and/or modulatory function in bone tissue.
 ...
PMID:Immunocytochemical demonstration of pituitary adenylate cyclase activating polypeptide (PACAP) in the porcine epiphyseal cartilage canals. 917 66

Specific receptors for pituitary adenylate cyclase-activating polypeptide (PACAP), a novel peptide with neuroregulatory and neurotrophic functions, have recently been identified in the retinas of different mammalian species. In the present study, expression of PACAP receptors and PACAP was investigated in the retinas of 12-18-week human embryos. Radioligand binding studies showed that the two forms of PACAP with 38 and 27 amino acids (PACAP 38 and PACAP 27, respectively) displaced the binding of 125I-PACAP 27 with IC50 values in the picomolar range, whereas functional receptor assays demonstrated that the two peptides were potent and effective stimulators of adenylyl cyclase activity. In contrast, vasoactive intestinal peptide (VIP) and human peptide histidine-isoleucine, which are homologous to PACAP, displayed lower affinities for the 125I-PACAP 27 binding site and were much less potent stimulators of cyclic AMP formation. Glucagon and secretin were inactive in both receptor assays. The expression of specific PACAP receptors was further investigated by reverse transcription-polymerase chain reaction technique, which showed the presence of mRNAs coding for PACAP type I and for nonselective PACAP type II (both VIP1 and VIP2) receptors. By the same technique, expression of PACAP mRNA was also detected. These data indicate that the developing human retina synthesizes PACAP and that the peptide may act on retinal cells by predominantly stimulating PACAP type I receptors coupled to cyclic AMP formation.
 ...
PMID:Expression of pituitary adenylate cyclase-activating polypeptide (PACAP) receptors and PACAP in human fetal retina. 928 45

Pituitary adenylate cyclase-activating polypeptide (PACAP) has been localized to pancreatic nerves and demonstrated to stimulate insulin and glucagon secretion in experimental animals. This study examined the occurrence and possible function of PACAP in the human pancreas. The content of PACAP27 was 0.44 +/- 0.04 pmol/g tissue, and that of PACAP38 was 29.6 +/- 6.4 pmol/g tissue in extracted human pancreas (n = 4). Furthermore, in a homogeneous group of seven healthy postmenopausal women, all aged 57 yr, iv infusion of synthetic human PACAP27 (3 pmol/kg.min for 75 min) increased basal levels of insulin, C peptide, and glucagon without significantly influencing basal glucose after 14 min. At 15 min, glucose was administered rapidly (0.3 g/kg, iv). The peak insulin after bolus glucose was 797 +/- 232 pmol/L during PACAP27 infusion vs. 559 +/- 164 pmol/L during saline infusion (P = 0.018). Also, the peak in C peptide after glucose was potentiated by PACAP27 (P = 0.018). In contrast, hepatic extraction, calculated as the C peptide/insulin molar ratio, was not significantly affected by PACAP27, and neither the glucose elimination rate nor reduction of serum insulin after the glucose-induced peak was changed by PACAP27. We conclude that PACAP occurs in human pancreas and stimulates insulin and glucagon secretion in humans. This suggests that PACAP is involved in the regulation of islet function in humans.
 ...
PMID:Pituitary adenylate cyclase-activating polypeptide stimulates insulin and glucagon secretion in humans. 928 50

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a novel bioactive peptide isolated from ovine hypothalamus. Recently, its presence and action have been demonstrated also in peripheral tissues such as testis and ovary. On the basis of sequence similarity, PACAP is included in the vasoactive intestinal peptide (VIP)/glucagon/secretin/growth hormone-releasing factor (GRF) family of neuropeptides. Because both VIP and GRF stimulate oocyte maturation in the rat ovary, we wanted to evaluate whether PACAP also could influence this process. Granulosa cells and follicle-enclosed, cumulus-enclosed, and denuded oocytes were obtained from immature eCG-treated rats. The addition of PACAP-38 significantly accelerated meiotic maturation in follicle- and cumulus-enclosed oocytes from treated rats and in follicle enclosed-oocytes from immature untreated rats, while VIP was effective only on follicle-enclosed oocytes. Interestingly, when used on denuded oocytes, PACAP was able to directly affect the meiotic process. In fact, the neuropeptide delayed oocyte maturation by maintaining elevated levels of intracellular cAMP. Our results clearly demonstrate an involvement of PACAP in oocyte meiotic maturation. Furthermore, for the first time, a direct effect of a peptide on the oocytes has been shown. Moreover, the differences in the action of PACAP and VIP on granulosa cells and oocytes suggest the presence of PACAP type I receptors on both cell types. Our results, along with the data demonstrating the presence of the peptide in the ovary, strongly suggest a potential relevance of PACAP in ovarian physiology.
 ...
PMID:Effect of pituitary adenylate cyclase-activating peptide on meiotic maturation in follicle-enclosed, cumulus-enclosed, and denuded rat oocytes. 936 73


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>