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)

1. The mechanisms underlying AVP-induced increase in [Ca(2+)](i) and glucagon release in clonal alpha-cells In-R1-G9 were investigated. 2. AVP increased [Ca(2+)](i) and glucagon release in a concentration-dependent manner. After the administration of AVP, glucagon was released within 30 s, quickly reached the maximum within 2 min, and maintained a steady-state concentration for at least 15 min. 3. In Ca(2+)-containing medium, AVP increased [Ca(2+)](i) in a biphasic pattern; a peak followed by a sustained plateau. In Ca(2+)-free medium, the Ca(2+) response to AVP became monophasic with lower amplitude and no plateau. Both the basal and AVP-induced glucagon releases were lower in the absence than in the presence of extracellular Ca(2+). When [Ca(2+)](i) was stringently deprived by BAPTA, a Ca(2+) chelator, AVP still significantly increased glucagon release. 4. Pretreatment with thapsigargin, a microsomal Ca(2+) ATPase inhibitor, abolished both the Ca(2+) peak and sustained plateau. 5.AVP increased intracellular concentration of IP(3). 6. U-73122 (8 microM), a phospholipase C inhibitor, abolished AVP-induced increases in [Ca(2+)](i), but only reduced AVP-induced glucagon release by 39%. 7. Pretreatment with nimodipine, an L-type Ca(2+) channel blocker failed to alter AVP-induced glucagon release or increase in [Ca(2+)](i). 8. The results suggest that AVP causes glucagon release through both Ca(2+)-dependent and -independent pathways. For the Ca(2+)-dependent pathway, the G(q) protein activates phospholipase C, which catalyzes the formation of IP(3). IP(3) induces Ca(2+) release from the endoplasmic reticulum, which, in turn, triggers Ca(2+) influx. Both Ca(2+) release and Ca(2+) influx may contribute to AVP-induced glucagon release.
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PMID:Mechanisms of AVP-induced glucagon release in clonal alpha-cells in-R1-G9: involvement of Ca(2+)-dependent and -independent pathways. 1069 31

Secretin, glucagon, gastric inhibitory polypeptide (GIP), and parathyroid hormone (PTH) belong, together with vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase (AC)-activating polypeptide, to a family of peptides (the VIP-secretin-glucagon family), which also includes growth hormone-releasing hormone and exendins. All the members of this peptide family possess a remarkable amino-acid sequence homology, and bind to G-protein-coupled receptors, whose signaling mechanism primarily involves AC/protein kinase A and phospholipase C/protein kinase C cascades. VIP and pituitary AC-activating polypeptide play a role in the regulation of the hypothalamus-pituitary-adrenal (HPA) axis, and in this review we survey findings that also other members of the VIP-secretin-glucagon family may have the same function. Secretin and secretin receptors are expressed in the hypothalamus and pituitary gland, and secretin inhibits adrenocorticotropic hormone (ACTH) release. No evidence is available for the presence of secretin receptors in adrenal glands, but secretin selectively depresses the glucocorticoid response to ACTH of dispersed zona fasciculata-reticularis (ZF/R) cells. Glucagon and glucagon-like peptide-1 are contained in the hypothalamus, and all the components of the HPA axis are provided with glucagon and glucagons-like-1 receptors. These peptides exert a short-term inhibitory effect on stress-induced pituitary ACTH release and depress the ZF/R cell response to ACTH by inhibiting the AC/protein kinase A cascade; they also stimulate hypothalamic arginine-vasopressin release. GIP receptors are present in the ZF/R of the normal adrenals, and are particularly abundant in some types of adrenocortical adenomas and hyperplasias. GIP, through the activation of the AC/protein kinase A cascade, evokes a sizeable glucocorticoid secretagogue effect, leading to the identification of a food/GIP-dependent Cushing's syndrome. PTH and PTH-related protein are expressed in the hypothalamus and pituitary gland, and PTH and PTH-related protein receptors in all the components of the HPA axis. Both peptides enhance ACTH and arginine-vasopressin release, as well as stimulate aldosterone and glucocorticoid secretion of dispersed zona glomerulosa and ZF/R cells, respectively. The involvement of growth hormone-releasing hormone and exendins in the functional regulation of the HPA axis has not yet been extensively investigated.
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PMID:Secretin, glucagon, gastric inhibitory polypeptide, parathyroid hormone, and related peptides in the regulation of the hypothalamus- pituitary-adrenal axis. 1076 61

The presence and functional significance of the extracellular calcium-sensing receptor (CaR) on human pancreatic beta-cells were investigated. Reverse transcriptase-polymerase chain reaction with primers for the extracellular domain of the CaR expressed in human parathyroid-secreting cells identified a product of the expected size in human pancreatic mRNA. Immunocytochemistry using an antibody against the extracellular region of CaR showed extensive immunoreactivity in insulin- and glucagon-containing cells but not in somatostatin-containing cells. In perifusion experiments, elevations in extracellular Ca2+ produced initial transient increases in insulin secretion, followed by a concentration-dependent and prolonged, but reversible, inhibition of secretion. Microfluorometric measurements of intracellular Ca2+ ([Ca2+]i) in isolated human beta-cells demonstrated that elevations in extracellular Ca2+ (0.5-10 mmol/l) caused rapid elevations in [Ca2+]i. Increases in extracellular Ca2+ caused small increases in the cyclic AMP content of whole human islets. These studies demonstrated that human beta-cells express an extracellular CaR and that activation of the receptor inhibits basal and nutrient-stimulated insulin secretion. The transduction mechanism that mediates this inhibitory effect is unknown, but our results suggest that it is unlikely to be through the adenylate cyclase-cyclic AMP pathway or through the phospholipase C-IP3 pathway. This CaR-mediated inhibitory mechanism may be an important autoregulatory mechanism in the control of insulin secretion.
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PMID:The extracellular calcium-sensing receptor on human beta-cells negatively modulates insulin secretion. 1086 62

Pituitary adenylate cyclase activating polypeptide (PACAP) is a novel member of the secretin-glucagon peptide family. In mammals, this peptide has been located in a wide range of tissues and is involved in a variety of biological functions. In lower vertebrates, especially fish, increasing evidence suggests that PACAP may function as a hypophysiotropic factor regulating pituitary hormone secretion. PACAP has been identified in the brain-pituitary axis of representative fish species. The molecular structure of fish PACAP is highly homologous to mammalian PACAP. The prepro-PACAP in fish, however, is distinct from that of mammals as it also contains the sequence of fish GHRH. In teleosts, the anterior pituitary is under direct innervation of the hypothalamus and PACAP nerve fibers have been identified in the pars distalis. Using the goldfish as a fish model, mRNA transcripts of PACAP receptors, namely the PAC1 and VPACI receptors, have been identified in the pituitary as well as in various brain areas. Consistent with the pituitary expression of PACAP receptors, PACAP analogs are effective in stimulating growth hormone (GH) and gonadotropin (GTH)-II secretion in the goldfish both in vivo and in vitro. The GH-releasing action of PACAP is mediated via pituitary PAC1 receptors coupled to the adenylate cyclase-cAMP-protein kinase A and phospholipase C-IP3-protein kinase C pathways. Subsequent stimulation of Ca2+ entry through voltage-sensitive Ca2+ channels followed by activation of Ca2+-calmodulin protein kinase II is likely the downstream mechanism mediating PACAP-stimulated GH release in goldfish. Although the PACAP receptor subtype(s) and the associated post-receptor signaling events responsible for PACAP-stimulated GTH-II release have not been characterized in goldfish, these findings support the hypothesis that PACAP is produced in the hypothalamus and delivered to the anterior pituitary to regulate GH and GTH-II release in fish.
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PMID:Pituitary adenylate cyclase activating polypeptide as a novel hypophysiotropic factor in fish. 1094 84

The distal tubule reabsorbs approximately 10% of the filtered Mg(2+), but this is 70-80% of that delivered from the loop of Henle. Because there is little Mg(2+) reabsorption beyond the distal tubule, this segment plays an important role in determining the final urinary excretion. The distal convoluted segment (DCT) is characterized by a negative luminal voltage and high intercellular resistance so that Mg(2+) reabsorption is transcellular and active. This review discusses recent evidence for selective and sensitive control of Mg(2+) transport in the DCT and emphasizes the importance of this control in normal and abnormal renal Mg(2+) conservation. Normally, Mg(2+) absorption is load dependent in the distal tubule, whether delivery is altered by increasing luminal Mg(2+) concentration or increasing the flow rate into the DCT. With the use of microfluorescent studies with an established mouse distal convoluted tubule (MDCT) cell line, it was shown that Mg(2+) uptake was concentration and voltage dependent. Peptide hormones such as parathyroid hormone, calcitonin, glucagon, and arginine vasopressin enhance Mg(2+) absorption in the distal tubule and stimulate Mg(2+) uptake into MDCT cells. Prostaglandin E(2) and isoproterenol increase Mg(2+) entry into MDCT cells. The current evidence indicates that cAMP-dependent protein kinase A, phospholipase C, and protein kinase C signaling pathways are involved in these responses. Steroid hormones have significant effects on distal Mg(2+) transport. Aldosterone does not alter basal Mg(2+) uptake but potentiates hormone-stimulated Mg(2+) entry in MDCT cells by increasing hormone-mediated cAMP formation. 1,25-Dihydroxyvitamin D(3), on the other hand, stimulates basal Mg(2+) uptake. Elevation of plasma Mg(2+) or Ca(2+) inhibits hormone-stimulated cAMP accumulation and Mg(2+) uptake in MDCT cells through activation of extracellular Ca(2+)/Mg(2+)-sensing mechanisms. Mg(2+) restriction selectively increases Mg(2+) uptake with no effect on Ca(2+) absorption. This intrinsic cellular adaptation provides the sensitive and selective control of distal Mg(2+) transport. The distally acting diuretics amiloride and chlorothiazide stimulate Mg(2+) uptake in MDCT cells acting through changes in membrane voltage. A number of familial and acquired disorders have been described that emphasize the diversity of cellular controls affecting renal Mg(2+) balance. Although it is clear that many influences affect Mg(2+) transport within the DCT, the transport processes have not been identified.
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PMID:Magnesium transport in the renal distal convoluted tubule. 1115 54

Pancreatic beta-cells from obese-hyperglycemic (ob/ob) mice are widely used for studying the mechanisms of insulin release, including its regulation by the cytoplasmic Ca2+ concentration ([Ca2+]i). In this study, we compared changes of [Ca2+]i in single beta-cells isolated from ob/ob mice with those from lean mice using dual-wavelength microfluorometry and the indicator fura-2. There were no differences in the frequency, amplitude, and half-width of the slow oscillations induced by glucose. Most beta-cells from the obese mice responded to 10 mM caffeine with transformation of the oscillations into sustained elevation of [Ca2+]i, a process counteracted by ryanodine. The beta-cells from the obese mice were characterized by ample generation of [Ca2+]i transients, which increased in number in the presence of glucagon. The transients became less frequent when leptin was added at a concentration as low as 1 nM. It is suggested that the excessive firing of [Ca2+]i transients in the ob/ob mice is owing to the absence of leptin and is mediated by activation of the phospholipase C signaling pathway.
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PMID:Pancreatic beta-cells from obese-hyperglycemic mice are characterized by excessive firing of cytoplasmic Ca2+ transients. 1157 29

A full biphasic insulin response is the most sensitive index for well-coupled beta-cell signal transduction. While first-phase insulin response is extremely sensitive to potentiating and inhibiting modulations, full expression of second-phase response requires near maximally activated beta-cell fuel metabolism. In the isolated rat pancreas, accelerated calcium entry or activation of protein kinase (PK)-A or PKC result in no insulin response in the absence of fuel metabolism. At submaximal levels of beta-cell fuel secretagogue, arginine (which promotes calcium entry) or glucagon (which activates PKA) produces a small first-phase insulin response but minimal or no second-phase response; carbachol (which activates PKC and promotes calcium entry) generates biphasic insulin response in the presence of minimal fuel (3.3 mmol/l glucose). Glucagon produces full biphasic response in the presence of 10.0 mmol/l glucose, whereas arginine requires near-maximal stimulatory glucose (16.7 mmol) to produce full biphasic insulin response. Thus, PKA and PKC signal pathways potentiate primary signals generated by fuel secretagogues to induce full biphasic insulin response, while calcium recruitment alone is insufficient to potentiate primary signals generated at low levels of fuel secretagogue. We suggest that three families of PKs (calmodulin-dependent PK [CaMK], PKA, and PKC) function as distal amplifiers for stimulus-secretion coupling signals originating from fuel metabolism, as well as from incretins acting through membrane receptors, adenylate cyclase, and phospholipase C. Several isoenzymes of PKA and PKC are present in pancreatic beta-cells, but the specific function of most is still undefined. Each PK isoenzyme is activated and subsequently phosphorylates its specific effector protein by binding to a highly specific anchoring protein. Some diabetes-related beta-cell derangements may be linked to abnormal function of one or more PK isoenzymes. Identification and characterization of the specific function of the individual PK isoenzymes may provide the tool to improve the insulin response of the diabetic patient.
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PMID:Beta-cell protein kinases and the dynamics of the insulin response to glucose. 1181 61

The mechanisms by which bradykinin (BK) increases glucagon release were investigated. BK (0.1-10 microM) increased [Ca(2+)](i) and glucagon release in clonal alpha-cells In-R1-G9. BK-induced glucagon release was lower in the absence than in the presence of extracellular Ca(2+), but it still increased glucagon release while [Ca(2+)](i) was stringently deprived. Depletion of intracellular Ca(2+) store with thapsigargin abolished both the BK-induced Ca(2+) peak and sustained plateau. Microinjection of heparin abolished BK-induced Ca(2+) release. Pertussis toxin (PTX) did not block BK-induced [Ca(2+)](i) increase or glucagon release. U-73122 (8 microM), a phospholipase C (PLC) inhibitor, abolished BK-induced increases in [Ca(2+)](i), but only reduced BK-induced glucagon release by 40%. A phospholipase D (PLD) inhibitor zLYCK reduced BK-induced glucagon release by 60%. The combination of U-73122 and zLYCK abolished BK-induced glucagon release. Both SK&F 96365, a receptor-operated Ca(2+) channel (ROC) blocker and nimodipine, an L-type Ca(2+) channel blocker, reduced BK-induced [Ca(2+)](i) increase and glucagon release. These findings suggest that BK increase glucagon release through a PTX-insensitive G protein and both Ca(2+)-dependent and -independent pathways. The Ca(2+)-dependent pathway is attributable to PLC activation. PLC catalyzes IP(3) formation, inducing Ca(2+) release from the endoplasmic reticulum, which, in turn, triggers Ca(2+) influx via both ROCs and L-type channels. PLD activation may be involved in Ca(2+)-dependent and/or -independent pathway.
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PMID:Mechanisms of bradykinin-induced glucagon release in clonal alpha-cells In-R1-G9: involvement of Ca(2+)-dependent and -independent pathways. 1208 64

Pituitary adenylate cyclase-activating polypeptide (PACAP) has been conserved remarkably during evolution and is widely expressed in the nervous system across phyla. PACAP has an amino acid sequence homology of 68% with that of vasoactive intestinal polypeptide (VIP) and of 37% with that of secretin, indicating that PACAP is a member of the VIP/glucagon/secretin superfamily. PACAP exerts its actions via three heptahelical G-protein-linked receptors: one PACAP-specific (PAC1) receptor and two receptors (VPAC1 and VPAC2) shared with VIP. PACAP stimulates several different signaling cascades in neurons, leading to the activation of adenylate cyclase, phospholipase C, and mitogen-activated protein kinase and mobilization of calcium. Although PACAP and VIP have no apparent homology with calcitonin and parathyroid hormone (PTH), PAC1, VPAC, secretin, glucagon, glucagon-like peptide 1, growth hormone-releasing hormone, calcitonin, and PTH/PTH-related peptide receptors are related to each other and constitute a subfamily of the G-protein-coupled receptors. Distribution analysis of PACAP and its receptors and pharmacological studies have elucidated its pleiotropic effects in the central and peripheral nervous systems. However, the relevance of the pharmacological PACAP effects to the actual physiological activities of endogenous PACAP has not been addressed, because potent and selective low-molecular-weight PACAP antagonists have not yet been developed. To assess the function of PACAP in vivo, we have recently generated PAC1 receptor- and PACAP-targeted mice, and provided evidence that PACAP plays a previously uncharacterized role in the regulation of psychomotor behaviors. In this review, we focus on the physiological and or pathophysiological roles mediated by PACAP in the nervous system.
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PMID:[Physiological significance of pituitary adenylate cyclase-activating polypeptide (PACAP) in the nervous system]. 1251 Mar 88

Peritoneal and bronchoalveolar macrophages activated in vitro by endotoxin, exhibit alterations in the acid phosphatase activity of cell lysates when certain hormones or autacoids are present in the culture medium. They also show morphological changes concerning general appearance and acid phosphatase cytochemistry. Certain agents known to increase the intracellular levels of cyclic AMP, such as dopamine and prostaglandin E2, decreased this enzyme activity in the lysates of peritoneal macrophages. Adrenalin had no effect on this activity at 14 hours, but was found to increase the activity in the culture medium at the initial hours of incubation. Glucagon decreased whereas insulin increased acid phosphatase activity in bronchoalveolar macrophages. Serotonin or histamine, known to activate phospholipase C, increased this activity in peritoneal or bronchoalveolar macrophages. The results of this study, taken together with previously published data (Kondomerkos et al., 2003), suggest that hormones and autacoids may control certain parameters of macrophage activation including acid phosphatase activity.
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PMID:In vitro effects of hormones and autacoids on the activity of acid phosphatase in the lysates of endotoxin-activated rat peritoneal and bronchoalveolar macrophages. 1297 79


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