Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Agonist-stimulated divalent cation entry was studied in fura-2-loaded hepatocytes. In the presence of extracellular Mn2+, the Ca2(+)-mobilizing hormone vasopressin produced a severalfold stimulation of the basal rate of fura-2 fluorescence quenching as a result of Mn2+ influx; this effect was blocked by the presence of Ni2+ in the incubation medium. Half-maximum and maximum stimulation of Mn2+ influx was observed with 0.1 and 0.8 nM vasopressin, respectively. Agonist-stimulated Mn2+ influx was also seen with angiotensin II, ATP, phenylephrine, and the combination of AlCl3 and NaF. The stimulation of Mn2+ influx did not occur immediately after addition of Ca2(+)-mobilizing agents, but was characterized by a latency period of 20-30 s. In contrast to vasopressin, glucagon did not stimulate Mn2+ influx into hepatocytes, but produced both a 3-fold enhancement of the rate of vasopressin-stimulated Mn2+ entry and the abolishment of the latency period. The effects of glucagon were mimicked by forskolin and dibutyryl cAMP. Pretreatment of hepatocytes with pertussis toxin or depolarization of the cells altered neither the basal rate of Mn2+ entry nor the ability of vasopressin to stimulate this rate. Emptying of the inositol 1,4,5-trisphosphate-sensitive Ca2+ store by treatment with 2,5-di-(tert-butyl)-1,4-benzohydroquinone (tBuBHQ) did not enhance Mn2+ entry into hepatocytes; however, exposure of the cells to tBuBHQ for 2 min markedly enhanced the ability of vasopressin, alone or in combination with glucagon, to increase the rate of Mn2+ influx. Furthermore, pretreatment with tBuBHQ for 2 min abolished the latency of vasopressin-stimulated Mn2+ influx. It is concluded that Ca2(+)-mobilizing hormones stimulate Ca2+ influx in hepatocytes, possibly through receptor-operated Ca2+ channels. The stimulation of divalent cation entry is transduced by a G protein, and the rate of influx appears to be controlled both by the intracellular level of cAMP and the empty state of an intracellular Ca2+ pool that may be inositol 1,4,5-trisphosphate-insensitive.
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PMID:Receptor-operated calcium influx in rat hepatocytes. Identification and characterization using manganese. 217 Mar 82

To clarify the role of the sympatho-adrenomedullary and renin-angiotensin-aldosterone systems, and catecholamine receptors, in the pathogenesis of orthostatic hypotension in diabetes mellitus (DM), urinary excretion of catecholamines, and plasma levels of norepinephrine (PNE), epinephrine (PE), renin activity (PRA), aldosterone (PAC), cyclic AMP (PcAMP) and cyclic GMP (PcGMP) were measured in 16 normal subjects (N) and 50 diabetic patients with or without orthostatic hypotension (DMOH(+), DMOH(-)). Changes in PNE, PE, PRA, PAC, PcAMP and PcGMP by standing, glucagon (G) administration and cold pressor test were examined. Furthermore, the effect of metoclopramide on catecholamine levels and blood pressure was investigated before and after cold pressor test. The results were following; (1) Urinary free norepinephrine excretion was significantly lower in DMOH(+), while urinary total norepinephrine excretion was normal in the two DM groups. Urinary free and total epinephrine excretions were lower in DMOH(+) than in N and DMOH(-). (2) PNE and PE were elevated after standing in all groups tested, and more pronounced in some cases of DMOH(+). Although PRA and PAC were elevated normally after standing in all groups, a dissociation between the two parameters was seen in some cases of DM. PcAMP after standing was correlated with PE(r = 0.829). Basal PcGMP was high in many cases of DMOH(+). However, no difference in the elevation of PcGMP after standing was noted between N and the two DM groups. (3) Systolic blood pressure (SBP) rose markedly in only DMOH(+) from 146 +/- 27mmHg to 178 +/- 34mmHg 5 minutes after G administration. The increment of PNE and PE 5 minutes after G administration were similar in all groups. In only DMOH(+), the increase in PcAMP 15 minutes after G test was proportional (r = 0.498) to that of epinephrine. (4) Responses of SBP, PNE, PE and PAC to cold pressor test apparently improved after administration of metoclopramide (MC) in some patients with DM. These results suggest that not only organic disturbance of sympathetic nerves but also functional inhibition of norepinephrine release mediated by dopamine receptor, may play an important role in the pathogenesis of orthostatic hypotension in diabetes mellitus. It is considered that catecholamine secretion from the adrenal medulla in DMOH(+) is increased by hypotension induced by standing. Furthermore, the vascular response to catecholamines may be accelerated through the increment of the extrajunctional receptor in DMOH(+).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[The role of the sympatho-adrenomedullary system and adrenergic receptors in the pathogenesis of orthostatic hypotension in diabetes mellitus]. 285 93

Treatment of isolated hepatocytes with NaF produced a concentration-dependent activation of phosphorylase, inactivation of glycogen synthase, efflux of Ca2+, rise in cytosolic free Ca2+ ([Ca2+]i), increase in myo-inositol-1,4,5,-P3 levels, decrease in phosphatidylinositol-4,5-P2 levels, and increase in 1,2-diacylglycerol levels. These changes were evident within 1 min and maximum at 2-5 min. Maximum effects on Ca2+ efflux, [Ca2+]i, glycogen synthase, and phosphorylase were observed with 15 mM NaF, whereas myo-inositol-1,4,5-P3 and 1,2-diacylglycerol levels were maximally stimulated by 50 mM NaF. The levels of intracellular cAMP were decreased by NaF (up to 10 mM) in the absence or presence of glucagon (0.1-1 nM) or forskolin (2 microM). The effects of low doses of NaF (2-15 mM) to inhibit basal or glucagon-stimulated cAMP accumulation, mobilize Ca2+, activate phosphorylase, and inactivate glycogen synthase were all potentiated by AlCl3. This potentiation was abolished by the Al3+ chelator deferoxamine. These results illustrate that AlF4- can mimic the effects of Ca2+-mobilizing hormones in hepatocytes and suggest that the coupling of the receptors for these hormones to the hydrolysis of phosphatidylinositol-4,5-P2 to myo-inositol 1,4,5-P3 is through a guanine nucleotide-binding regulatory protein. This is because AlF4- is known to modulate the activity of other guanine nucleotide regulatory proteins (Ni, Ns, and transducin).
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PMID:Role of a guanine nucleotide-binding regulatory protein in the hydrolysis of hepatocyte phosphatidylinositol 4,5-bisphosphate by calcium-mobilizing hormones and the control of cell calcium. Studies utilizing aluminum fluoride. 299 9

As the brain develops, a homogeneous population of mitotically active progenitors generates the molecularly heterogeneous post-mitotic cells of the mature brain. The balance between cell division, growth arrest and differentiation of these progenitors undoubtedly requires the activation of a vast array of genes. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a member of the vasoactive intestinal polypeptide (VIP)/secretin/glucagon family. Within the nervous system, PACAP has been shown to stimulate neurite outgrowth, regulate neurotransmitter production and neuronal survival. These diverse biological actions are mediated through interaction with two types of receptors, a PACAP-selective receptor (PAC(1)-R) and receptors which interact almost equally with both VIP and PACAP. Since several lines of evidence suggest that PACAP acts as a neurotrophic factor, we sought to characterize PACAP and PAC(1)-R expression in the developing rat nervous system. The PAC(1)-R is expressed at very high levels in ventricular zones throughout the neuraxis. In addition to the embryonic enrichment in proliferative zones, PAC(1)-R expression is maintained in areas of neurogenesis in the adult central nervous system (CNS), namely, the subventricular zone of the olfactory bulb and hippocampal dentate gyrus. In contrast, PACAP is expressed primarily in the post-mitotic parenchyma. This temporal regulation and cellular distribution suggests that PACAP, through its interaction with the PAC(1)-R, may play a role in mammalian neurogenesis.
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PMID:Developmental regulation of pituitary adenylate cyclase-activating polypeptide and PAC(1) receptor mRNA expression in the rat central nervous system. 1072 27

Pituitary adenylate cyclase-activating polypeptide (PACAP) was originally isolated from the ovine brain in 1989 as a novel hypothalamic hormone that potently activates adenylate cyclase to produce cyclic AMP in pituitary cells. This neuropeptide belongs to the secretin/glucagon/vasoactive intestinal peptide (VIP) superfamily, and exists in two amidated forms as PACAP38 (38-amino acid residues) and PACAP27 derived from the same precursor. The primary structure of PACAP has been remarkably conserved throughout evolution among tunicata, ichthyopsida, amphibia and mammalia, and a PACAP-like neuropeptide has also been determined in Drosophila. Both PACAP and its receptors are mainly distributed in the nervous and endocrine systems showing pleiotropic functions with high potency. There are three types of receptors with high PACAP-binding affinity and with different tissue-distribution patterns. All of them belong to G-protein-coupled receptor superfamily with seven transmembrane domains. PAC(1) is the PACAP-specific receptor and exists in at least eight splice variants which couple to different intracellular signal transduction pathways. VPAC(1) and VPAC(2) are the common receptors for both PACAP and VIP, which are coupled to adenylate cyclase. This review article presents and discusses an update on PACAP research and its pleiotropic physiological functions based on multiple receptor-mediated signaling mechanisms in both the central and peripheral nervous system, including the regulation of hypothalamic neurosecretion, homeostatic control of circadian clock and behavioral actions, involvement in learning and memory processes, neuroprotective effects such as anti-apoptosis and response to injury and inflammation, and neural ontogenetic functions on proliferation/differentiation processes from early stages.
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PMID:PACAP and its receptors exert pleiotropic effects in the nervous system by activating multiple signaling pathways. 1237 5

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a novel member of the secretin/glucagon/vasoactive intestinal peptide (VIP) superfamily. In vertebrates, including avians, it occurs in two forms: PACAP(38) and PACAP(27). PACAP structure is well conserved during evolution, being identical in mammals, and showing one amino acid dfifference in avians (chick, turkey). PACAP is widely distributed in the central nervous system and peripheral tissues and displays a pleiotropic activity, including functions as a hypophysiotropic hormone, neuromodulator, and neurotrophic factor. PACAP exerts its biological actions through three types of receptors designated PAC(1), VPAC(1) and VPAC(1). This review (1) presents the current knowledge on PACAP origin, distribution and function, (2) compares the avian findings with those found in mammals, and (3) describes receptor-linked mechanisms in avians, including recent data on receptor-related signal transduction pathways, with a special emphasis on receptor pharmacology and function.
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PMID:PACAP in avians: origin, occurrence, and receptors--pharmacological and functional considerations. 1257 Aug 10

The aim of the present study was to characterize the effects of pituitary adenylate cyclase activating polypeptide (PACAP) on the endocrine pancreas in anesthetized dogs. PACAP(1-27) and a PACAP receptor (PAC(1)) blocker, PACAP(6-27), were locally administered to the pancreas. PACAP(1-27) (0.005-5 microg) increased basal insulin and glucagon secretion in a dose-dependent manner. PACAP(6-27) (200 microg) blocked the glucagon response to PACAP(1-27) (0.5 microg) by about 80%, while the insulin response remained unchanged. With a higher dose of PACAP(6-27) (500 microg), both responses to PACAP(1-27) were inhibited by more than 80%. In the presence of atropine with an equivalent dose (128.2 microg) of PACAP(6-27) (500 microg) on a molar basis, the insulin response to PACAP(1-27) was diminished by about 20%, while the glucagon response was enhanced by about 80%. The PACAP(1-27)-induced increase in pancreatic venous blood flow was blocked by PACAP(6-27) but not by atropine. The study suggests that the endocrine secretagogue effect of PACAP(1-27) is primarily mediated by the PAC(1) receptor, and that PACAP(1-27) may interact with muscarinic receptor function in PACAP-induced insulin and glucagon secretion in the canine pancreas in vivo.
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PMID:Effects of PACAP(1-27) on the canine endocrine pancreas in vivo: interaction with cholinergic mechanism. 1289 20

We have demonstrated previously in primary cultures of mouse cerebellar granule cells (CGCs) that endogenously synthesized pituitary adenylate cyclase-activating polypeptide (PACAP) contributes at least in part to the activity-dependent survival of CGCs (Tabuchi et al. [2001] Neurosci. Res. 39:85-93). In this study, we have demonstrated that expression of vasoactive intestinal polypeptide (VIP), a member of the same VIP/secretin/glucagon family as PACAP, was activated markedly by Ca(2+) influx through L-type voltage-dependent Ca(2+) channels (L-VDCCs), which could be induced under the depolarizing condition induced by high concentration of potassium (K(+)) in the medium. The activation of VIP mRNA expression, different from that of PACAP, was dependent partly on de novo protein synthesis. On the other hand, mRNA expression of secretin and PACAP/VIP receptors (PAC(1), VPAC(1), and VPAC(2)) was not activated by the Ca(2+) influx; rather, PAC(1) mRNA expression was reduced. Exogenously added VIP prevented apoptosis of CGCs under nondepolarizing conditions, the effect of which was mediated specifically through the VPAC(1) receptor. Furthermore, the survival of CGCs under depolarizing conditions could be mediated partly through VPAC(1), the contribution of which was much less than that of PAC(1). These findings indicate that PACAP and VIP genes are coordinately activated by the Ca(2+) signals in CGCs, but the contribution of VIP to the activity-dependent survival of CGCs is quite small.
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PMID:Calcium signal-mediated expression of the vasoactive intestinal polypeptide gene and its small contribution to activity-dependent survival of mouse cerebellar granule cells. 1519 36

Pituitary adenylate cyclase-activating polypeptide (PACAP), a member of the glucagon/secretin peptide family, has been recently proposed to be the ancestral GH-releasing factor. Using grass carp as a model for bony fish, we examined the mechanisms for PACAP regulation of GH synthesis and secretion at the pituitary level. Nerve fibers with PACAP immunoreactivity were identified in the grass carp pituitary overlapping with the distribution of somatotrophs. At the somatotroph level, PACAP was shown to induce cAMP synthesis and Ca(2+) entry through voltage-sensitive Ca(2+) channels (VSCC). In carp pituitary cells, PACAP but not vasoactive intestinal polypeptide increased GH release, GH content, total GH production, and steady-state GH mRNA levels. PACAP also enhanced GH mRNA stability, GH promoter activity, and nuclear expression of GH primary transcripts. Increasing cAMP levels, induction of Ca(2+) entry, and activation of VSCC were all effective in elevating GH secretion and GH mRNA levels. PACAP-induced GH secretion and GH mRNA expression, however, were abolished by inhibiting adenylate cyclase and protein kinase A, removing extracellular Ca(2+) or VSCC blockade, or inactivating calmodulin (CaM)-dependent protein kinase II (CaM kinase II). Similar sensitivity to VSCC and CaM kinase II blockade was also observed by activating cAMP production as a trigger for GH release and GH gene expression. These results suggest that PACAP stimulates GH synthesis and secretion in grass carp pituitary cells through PAC(1) receptors. These stimulatory actions probably are mediated by the adenylate cyclase/cAMP/protein kinase A pathway coupled to Ca(2+) entry via VSCC and subsequent activation of CaM/CaM kinase II cascades.
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PMID:Pituitary adenylate cyclase-activating polypeptide (PACAP) as a growth hormone (GH)-releasing factor in grass carp. I. Functional coupling of cyclic adenosine 3',5'-monophosphate and Ca2+/calmodulin-dependent signaling pathways in PACAP-induced GH secretion and GH gene expression in grass carp pituitary cells. 1612 57

Islet function is regulated by a number of different signals. A main signal is generated by glucose, which stimulates insulin secretion and inhibits glucagon secretion. The glucose effects are modulated by many factors, including hormones, neurotransmitters and nutrients. Several of these factors signal through guanine nucleotide-binding protein (G protein)-coupled receptors (GPCR). Examples of islet GPCR are GPR40 and GPR119, which are GPCR with fatty acids as ligands, the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), the receptors for the islet hormones glucagon and somatostatin, the receptors for the classical neurotransmittors acetylcholine (ACh; M(3) muscarinic receptors) and noradrenaline (beta(2)- and alpha(2)-adrenoceptors) and for the neuropeptides pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP; PAC(1) and VPAC(2) receptors), cholecystokinin (CCK(A) receptors) and neuropeptide Y (NPY Y1 receptors). Other islet GPCR are the cannabinoid receptor (CB(1) receptors), the vasopressin receptors (V1(B) receptors) and the purinergic receptors (P(2Y) receptors). The islet GPCR couple mainly to adenylate cyclase and to phospholipase C (PLC). Since important pharmacological strategies for treatment of type 2 diabetes are stimulation of insulin secretion and inhibition of glucagon secretion, islet GPCR are potential drug targets. This review summarizes knowledge on islet GPCR.
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PMID:G-protein-coupled receptors and islet function-implications for treatment of type 2 diabetes. 1790 Jul


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