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: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have reviewed the literature, which supports an important role for dopamine withdrawal in the regulation of PRL secretion. Concentrations of dopamine in the hypophyseal portal circulation are sufficient to occupy the majority of dopamine receptors (1) and tonically suppress PRL secretion (20-26). Brief escapes from dopaminergic regulation associated with the secretion of PRL have been observed (37-41). Therefore, dopamine regulates secretion of PRL both by occupancy of, as well as dissociation from, specific D2 dopamine receptors. The rapid off rate from its receptor (2) is consistent with signals transmitted through brief decreases in dopamine concentration. The removal of dopamine for 10 min results in increases in intracellular cAMP and presumably activation of protein kinase A (39, 138) as well as activation of phospholipase C (137, 138) and protein kinase C (136). The removal of dopamine results directly in the release of PRL (37-41). Furthermore, the brief removal of dopamine results in the long-term potentiation of the PRL-releasing action of TRH (38-40). The potentiating action of dopamine withdrawal appears to be mediated by the activation of protein kinase A since pretreatment with VIP, a hormone that signals via protein kinase A, also potentiates the action of TRH (39). TRH stimulates PRL release via Ca2+/protein kinase C (177-184). The potentiating action of dopamine removal is selective for the Ca2+/protein kinase C pathway since dopamine removal does not potentiate the PRL-secreting action of VIP (38, 87, 92). The action of TRH is potentiated up to 30 min after the return of dopamine and the suppression of PRL to basal levels (38). In Fig. 10, dopamine dissociation from its receptor or VIP association to its receptor are shown separated by a broken line to indicate that by the time the potentiation of the action of TRH is tested, either dopamine is again occupying its receptor or VIP is no longer present. Therefore, the effect of protein kinase A activation is remembered by the lactotroph. We hypothesize that the responsiveness of the cell to TRH is potentiated by the phosphorylation of proteins by protein kinase A. Two potential substrates for protein kinase A are voltage-dependent Ca2+ channels and protein phosphatase inhibitors that would prolong the action of protein kinase C. When TRH occupies its receptor, intracellular Ca2+ levels are increased first from intracellular stores and subsequently by extracellular Ca2+ influx (187-189). Intracellular Ca2+ is mobilized by increased levels of IP3(128). Extracellular Ca2+ enters the lactotroph via voltage-dependent Ca2+ channels (189, 190).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Dissociation of dopamine from its receptor as a signal in the pleiotropic hypothalamic regulation of prolactin secretion. 161 63

We used thapsigargin (TG), 2,5-di-tert-butyl-1,4-benzohydroquinone (BHQ) and cyclopiazonic acid (CPA), each of which inhibits microsomal Ca(2+)-ATPase, to evaluate the effects of this inhibition on cytoplasmic free calcium ([Ca2+]i) and secretagogue-stimulated enzyme secretion in rat pancreatic acini. Using single-cell microspectrofluorimetry of fura-2-loaded acini we found that all three agents caused a sustained increase in [Ca2+]i by mobilizing calcium from inositol-(1,4,5)-trisphosphate-sensitive intracellular calcium stores and by promoting influx of extracellular calcium. Concentrations of all three agents that increased [Ca2+]i potentiated the stimulation of enzyme secretion caused by secretagogues that activate adenylate cyclase but inhibited the stimulation of enzyme secretion caused by secretagogues that activate phospholipase C. With BHQ, potentiation of adenylate cyclase-mediated enzyme secretion occurred immediately whereas inhibition of phospholipase C-mediated enzyme secretion occurred only after several min of incubation. In addition, the effects of BHQ and CPA on both [Ca2+]i and secretagogue-stimulated enzyme secretion were reversed completely by washing whereas the actions of TG could not be reversed by washing. Concentrations of BHQ in excess of those that caused maximal changes in [Ca2+]i inhibited all modes of stimulated enzyme secretion by a mechanism that was apparently unrelated to changes in [Ca2+]i. Finally, in contrast to the findings with TG and BHQ, CPA inhibited bombesin-stimulated enzyme secretion over a range of concentrations that was at least 10-fold lower than the range of concentrations over which CPA potentiated VIP-stimulated enzyme secretion.
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PMID:Effect of inhibition of microsomal Ca(2+)-ATPase on cytoplasmic calcium and enzyme secretion in pancreatic acini. 750 54

Calcium and phosphorus metabolism is mainly regulated by PTH through its actions on kidney and bone. PTHrP, which is associated with the hypercalcemia of malignancy syndrome, binds to and activates the same receptor that PTH does. cDNA clones of PTH/PTHrP receptors from rat osteosarcoma (ROS 17/2.8) and opossum kidney (OK) cells are highly homologous and are members of a novel G protein-linked receptor family that includes calcitonin, glucagon, GLP-1, GHRH, VIP, and secretin receptors. Analysis of the protein sequence predicts a receptor with 7 transmembrane domains, a 155 amino acids (aa) extracellular (EC) N-terminal, and 130aa intracellular C-terminal domaina. The extracellular domain has 6 conserved cysteines and 4 potential glycosylation sites. When transfected in COS cells, both receptors are able to bind PTH and PTHrP active fragments with equal affinity. Likewise, agonists activate both adenylate cyclase and phospholipase C efficiently. The N-terminal EC domain and the first EC loop seem to determine the receptor binding capacity with the agonists. Activation of adenylate cyclase and phospholipase C might involve multiple sites between the 3rd helix and the C-terminal tail. Partial characterization of the rat PTH/PTHrP receptor gene demonstrates the existence of at least 15 exons. The first six transmembrane domains are encoded by separated exons. The PTH/PTHrP receptor mRNA is expressed mainly in kidney and bone, and also is widely expressed in many tissues, but not all. A major 2.3-2.5 kb transcript is observed in all these tissues. Nevertheless, 2 larger transcripts are observed in kidney and liver, and multiple smaller mRNA species are observed in kidney, skin, and testis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Mode of action of parathyroid hormone (PTH) and PTH-related peptide (PTHrP) in target organs]. 785 77

Among vertebrates, there is an extreme conservation in amino acid sequence for the neuropeptide PACAP-38 and its C-terminal shortened derivative PACAP-27. The PACAP gene is assigned to chromosome 18 in man and its organization has been characterized. PACAP-38 and its minor derivative PACAP-27 are widely distributed in the central nervous system. PACAP-38 is particularly abundant in hypothalamus. The mapping of the afferentation and efferentation of PACAP systems are progressively delineated, including a search for the colocalization with other neurotransmitters. In several peripheral organs positive neuronal perikarya and fibers are also seen. PACAP acts through two types of receptors: (1) the highly selective type I that displays a 500 to 2000 selectivity for PACAP-38 and PACAP-27 as compared to VIP; (2) type II is the so-called VIP receptor showing similar high affinity for PACAP-38, PACAP-27 and VIP. It is less selective, therefore, than previously thought. This is why this second receptor, qualifying as an unspecific VIP-PACAP receptor, is hardly considered here. Type I receptors can stimulate two enzymes: the adenylate cyclase and phospholipase C (whose activation leads to the inositol phosphate-cytosolic Ca2+ cascade). This dual coupling may have several distal consequences including on gene expression, cell growth and differentiation. Although a relatively comprehensive spectrum of pharmacological activities has already been established we still need to limit the physiological roles of PACAP as neurotransmitter and/or neuromodulator. Concerning the hypothalamo-pituitary axis, PACAP reduces food intake in mice and raises plasma arginine vasopressin in rat, probably through PACAP-ir neurons in paraventricular and supraoptic nuclei projecting to the neurohypophysis. PACAP originating in the hypothalamus may also be transported to the anterior pituitary through portal vessels. Data on the antehypophysis suggest a role on i.a. reproduction and growth. PACAP stimulates adenylate cyclase and increases [Ca2+] in gonadotropes, somatotropes, and folliculo-stellate cells. It elevates the secretion of alpha-MSH from melanotropes, and that of interleukin-6 from pituitary folliculo-stellate cells. PACAP potentiates the effects of LHRH on LH and FSH secretion. More clearly perhaps, PACAP increases the synthesis of LH, GH, PRL and ACTH after 1-2 days. In human pathology, PACAP-27 and PACAP-38 stimulate adenylate cyclase activity in membranes from 'null'-, gonadotropin-, GH-, and ACTH-producing pituitary adenomas but are inactive in prolactinomas.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Type I receptors for PACAP (a neuropeptide even more important than VIP?). 821 37

In order to determine whether tachykinins alter the function of chief cells and to characterize the receptors mediating the effect, we investigated the abilities of various substance P (SP)-related peptides to inhibit the binding of 125I-Bolton-Hunter labeled substance P (125I-BH-SP) and their abilities to alter cell function in dispersed chief cells from guinea pig stomach. Binding of 125I-BH-SP was saturable, reversible, time- and temperature-dependent and was inhibited by several SP-related peptides with relative potencies of SP = physalaemin (IC50:0.19 nM) > SP methyl ester (SP-ME) (IC50:3.3 nM) > eledoisin (IC50:6.1 nM) > neurokinin A (NKA) (IC50: 65 nM) > neurokinin B (NKB) (IC50:80 nM). Analyses of these binding data demonstrated that chief cells possess a high and low affinity class of binding sites. Neither 125I-NKA nor [phenylalanyl-3,4,5-3H]senktide demonstrated saturable binding to chief cells. Acid stripping experiments demonstrated rapid ligand internalization with 55% of the bound radioligand internalized by 10 min. Phospholipase C activating agents (carbachol, CCK-8), adenylate cyclase activating agents (secretin, VIP), TPA and the calcium ionophore, A23187, all inhibited the binding of 125I-BH-SP and it was due to inhibition of ligand internalization with no change in surface bound parameters. SP (0.1 microM) stimulated pepsinogen secretion but was 4-times less efficacious than CCK-8 (10 nM) or carbachol (1 mM). 10 nM SP stimulated a rapid increase in cytoplasmic free calcium concentration ([Ca2+]i) followed by a sustained elevation lasting 2 min. Single cell spectroscopy demonstrated SP (10 pM to 1 microM) did not cause calcium oscillations. The NK1 receptor antagonist, CP96,345 specifically inhibited the SP-stimulated changes in [Ca2+]i and pepsinogen secretion. The relative potencies of SP-related peptides to stimulate pepsinogen secretion and [Ca2+]i demonstrated a close agreement with their abilities to inhibit the binding of 125I-BH-SP, and comparison of the dose-response curves suggests occupation of the low affinity sites mediate changes in biologic activity. In conclusion, the present study demonstrates that chief cells possess a NK1 subtype of tachykinin receptor, occupation of the low affinity sites of this receptor cause calcium mobilization and pepsinogen secretion, and that binding to this receptor is regulated by agents that activate phospholipase C, adenylate cyclase, protein kinase C and calcium mobilization.
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PMID:Gastric chief cells possess NK1 receptors which mediate pepsinogen secretion and are regulated by agents that increase cAMP and phospholipase C. 867 32

The presence of the pertussis toxin (PTX) insensitive GTP-binding proteins (C-proteins) G(q) alpha and/or G(11) alpha has been demonstrated in three different prolactin (PRL) and growth hormone (GH) producing pituitary adenoma cell lines. Immunoblocking of their coupling to hormone receptors indicates that G(q) and/or G(11) confer throliberin (TRH) responsive phospholipase C (PL-C) activity in these cells. The contention was substantiated by immunoprecipitation analyses showing that anti G(q)/11 alpha-sera coprecipitated PL-C activity. In essence, only G(q)/11 (but neither G(12) G(13) nor G(o)) seems to mediate the TRH-sensitive PL-C activity, while G(o) may be coupled to a basal or constitutive PL-C activity. Immunoblocking studies imply that the B gamma-complex also, to some extent, may stimulate GH(3) pituitary cell line PL-C activity. Finally, the steady state levels of G(q)/(11) alpha mRNA and protein were down regulated upon long term exposure of the GH(3) cells to TRH (but not to vasoactive intestinal peptide = VIP).
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PMID:Phospholipase C activation in rat pituitary adenoma (GH) cells. 886 41

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.
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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

The current studies have implicated a prominent role for PACAP peptides in modulating the physiological function of cells derived from the sympathoadrenal lineage. Compared to VIP, both PACAP-27 and PACAP-38 demonstrated potent, efficacious, and sustained stimulatory effects on sympathetic neuronal NPY and catecholamine production. The differential effects of PACAP peptides on SCG NPY and catecholamine content and secretion coincided with previous studies that activated directly the sympathetic intracellular cyclic AMP-protein kinase A signaling pathway. These effects appear to be mediated primarily by PACAP1 receptor splice variants coupled to both adenylyl cyclase and phospholipase C in SCG neurons. The actions of PACAP peptides in the SCG shared many parallels with adrenal medullary chromaffin cells, suggesting diverse roles for the PACAP peptidergic system in sympathoadrenal cell development and function. Rather than solutions, these results pose additional questions for the future. What are the endogenous sources of PACAP that regulate sympathetic and adrenal function? Do PACAP peptides, like VIP, have dual roles and also act as sympathetic postganglionic neuromodulators? Are VIP/PACAP receptors expressed during SCG development? What regulates sympathetic PACAP1 receptor isoform expression and how are they differentially coupled to neuronal intracellular signaling cascades? What defines the tissue-specific responses to PACAP-27 and PACAP-38? While many of these questions are not easily approached, future studies of these issues will certainly illuminate the function of PACAP and PACAP receptors in the nervous and endocrine systems.
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PMID:Pituitary adenylate cyclase-activating polypeptides, PACAP-38 and PACAP-27, regulation of sympathetic neuron catecholamine, and neuropeptide Y expression through activation of type I PACAP/VIP receptor isoforms. 899 4

Recent studies suggest that in some tissues GRP receptor activation can both stimulate phospholipase C and the adenylate cyclase pathway and that activation of the latter pathway may be important in mediating some of its well-described growth effects. However, other studies suggest GRP-R may not be coupled to adenylate cyclase. To investigate this possibility, in the present study we determined the coupling of the GRP receptors to each pathway in mouse, rat, and guinea pig pancreatic acini and compared it to that in mouse Swiss 3T3 cells and human SCLC cells, all of which possess well-characterized GRP receptors. Moreover, we tested the effect of PKC activation on the ability of GRP-related peptides to increase cAMP accumulation in these tissues. Changes in cAMP levels were determined with or without IBMX present, with or without forskolin, or both to amplify small increases in cAMP. In mouse, rat and guinea pig pancreatic acini, murine Swiss 3T3 cells and human SCLC cells, GRP-related peptides caused a 600%, 500%, 250%, 300% and 60% increase, respectively, in [3H]IP with 1-3 nM causing a half-maximal effect. In murine Swiss 3T3 cells, IBMX, forskolin, and IBMX plus forskolin caused a 300%, 3500% and 10500% increase in cAMP, respectively. GRP-related peptides and VIP caused an additional 70% increase in cAMP with GRP causing a half-maximal (EC50) increase in cAMP at 2.1 +/- 0.5 nM, which was not significantly different from the EC50 of 3.1 +/- 0.9 nM for increasing [3H]IP in these cells. GRP-related peptides did not stimulate increases in cAMP in mouse, rat or guinea pig pancreatic acini or in SCLC cells either alone, with IBMX or forskolin or both. However, in pancreatic acini IBMX, forskolin or both increased cAMP 3 to 8-, 10 to 500-, and 100 to 1000-fold increase and the addition of VIP caused an additional 20-, 2-, and 3-fold increase in cAMP in the different species. In mouse pancreatic acini with TPA alone or IBMX plus TPA, neither bombesin nor GRP increased cAMP. Furthermore, in mouse pancreatic acini, neither TPA nor TPA plus IBMX altered basal or VIP-stimulated increases in cAMP. In mouse Swiss 3T3 cells TPA significantly increased cAMP stimulated by Bn, GRP or VIP. These results demonstrated that GRP receptor activation in normal tissues from three different species and a human tumoral cell line do not result in adenylate cyclase activation, whereas in Swiss 3T3 cells it causes such activation. The results suggest that the difference in coupling to adenylate cyclase is likely at least partially due to a difference in coupling to an adenylate cyclase subtype whose activation is regulated by PKC. Therefore, the possible growth effects mediated by this receptor in different embryonic or tumoral cells through activation of adenylate cyclase are not likely to be an important intracellular pathway for these effects in normal tissues.
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PMID:The gastrin-releasing peptide receptor is differentially coupled to adenylate cyclase and phospholipase C in different tissues. 919 77

The PACAP receptor (PACAP I receptor, selective for PACAP) and the PACAP II VIP1 receptor (recognizing PACAP and VIP with the same high affinity) were stably expressed in Chinese Hamster Ovary (CHO) cells. Cell lines expressing different receptor densities, as measured by binding saturation curves, were selected. Inositol phosphate production was stimulated dose dependently in all the cell lines by PACAP and VIP, and the order of potency of the agonists was identical to that of high affinity receptor occupancy. The stimulatory effect of a saturating peptide concentration was proportional to the total receptor density. At similar receptor densities, however, the PACAP receptor mediated stimulation was higher than the VIP receptor-mediated stimulation. Pretreatment of the cells with pertussis toxin for 8 h had no effect on receptor densities, did not alter the PACAP stimulated inositol phosphate synthesis by the cells expressing the PACAP I receptor but markedly inhibited the response of the cells expressing the PACAP II VIP1 receptor. Thus, the present results indicate that the two G(s)-coupled PACAP I and PACAP II VIP1 receptors may stimulate IP production. The maximal stimulation depended on the number of receptor expressed; the PACAP I and PACAP II VIP1 receptors probably activated the phospholipase C through G proteins of the G(q), and of the G(i)/G(o) families, respectively.
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PMID:The pituitary adenylate cyclase activating polypeptide (PACAP I) and VIP (PACAP II VIP1) receptors stimulate inositol phosphate synthesis in transfected CHO cells through interaction with different G proteins. 922 29


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