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)

Dopamine receptors of D2 type present on lactotroph cells are coupled to a large series of transduction mechanisms. Beside their negative coupling with adenylate cyclase, they are also coupled with potassium and calcium channels, leading to a decreased intracellular calcium concentration. In addition, D2 dopamine receptors also modulate phospholipase activities. Dopamine inhibits inositol phosphate production, through two distinct mechanisms. One of them could represent a direct negative coupling with phospholipase C. All these transduction mechanisms of the D2 dopamine receptors implicate G proteins sensitive to pertussis toxin. In contrast, these receptors are negatively coupled to phospholipase A2 through G proteins insensitive to this toxin. Both isoforms of the D2 dopamine receptor, generated by alternate splicing of a single gene, are present in lactotroph cells. After transfection in CH4C1 cells the two isoforms are coupled with adenylate cyclase while only the shortest isoform appears negatively coupled to phospholipase C. Functional D2 dopamine receptors are present in human prolactinomas. Resistance to bromocriptine therapy is associated with a decreased density of these receptors in the tumor. In addition, the ratio of the two receptor isoforms (measured by PCR) is different in responsive and resistant tumors. Furthermore, the activity of Gi/Go proteins coupled to adenylate cyclase appears also affected in resistant tumors. Resistance to bromocriptine therapy appears thus to involve multiple changes at the different levels of the multiple mechanisms of action of dopamine on lactotroph cells.
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PMID:D2 dopaminergic receptors: normal and abnormal transduction mechanisms. 130 22

Dopamine receptors of DA-1 and DA-2 subtypes are localized in various regions within the kidney including the renal vasculature (DA-1) as well as sympathetic nerve terminals innervating the renal blood vessels (DA-2). More recent studies using receptor-ligand binding and receptor autoradiography have shown that DA-1 receptors are localized at both the luminal and basolateral membranes at the level of the proximal tubules. Activation of these DA-1 receptors by dopamine and by selective DA-1 receptor agonists results in natriuresis and diuresis. The cellular signaling mechanisms responsible for this response appear to be DA-1 receptor-induced activation of adenylate cyclase and phospholipase C, which via the generation of various intracellular messenger systems cause inhibition of Na(+)-H+ antiport (luminal) and Na+, K(+)-ATPase (basolateral), respectively. Both of these events consequently inhibit sodium reabsorption leading to natriuresis and diuresis. It is also known that dopamine can be synthesized within proximal tubular cells from L-dopa, which is taken up from the tubular lumen, and this locally produced dopamine plays an important role in the regulation of sodium excretion particularly during increases in sodium intake. Furthermore, a defect in the renal dopaminergic mechanism may be one of the pathogenic factors in certain forms of hypertension. Finally, whereas DA-1 receptor agonists are shown to be of therapeutic benefit in the treatment of hypertension, heart failure, and acute renal failure, some selective DA-2 receptor agonists are effective antihypertensive agents.
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PMID:Anatomical distribution and function of dopamine receptors in the kidney. 168 44

Understanding the actions of the neurotransmitter dopamine in the brain is important in view of its roles in neuropsychiatric illnesses. Dopamine D1 receptors, which stimulate both adenylyl cyclase and phospholipase C, and D2 receptors, which inhibit them, can nevertheless act synergistically to produce many electrophysiological and behavioral responses. Because this functional synergism can occur at the level of single neurons, another, as yet unidentified, signalling pathway activated by dopamine has been hypothesized. We report here that in Chinese hamster ovary (CHO) cells transfected with the D2 receptor complementary DNA, D2 agonists potently enhanced arachidonic acid release, provided that such release has been initiated by stimulating constitutive purinergic receptors or by increasing intracellular Ca2+. In CHO cells expressed D1 receptors, D1 agonists exert no such effect. When D1 and D2 receptors are coexpressed, however, activation of both subtypes results in a marked synergistic potentiation of arachidonic acid release. The numerous actions of arachidonic acid and its metabolites in neuronal signal transduction suggest that facilitation of its release may be implicated in dopaminergic responses, such as feedback inhibition mediated by D2 autoreceptors, and may constitute a molecular basis for D1/D2 receptor synergism.
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PMID:Dopamine activation of the arachidonic acid cascade as a basis for D1/D2 receptor synergism. 190 71

Stimulation of phosphoinositide-specific phospholipase C (PLC) by muscarinic cholinergic and serotoninergic agonists was measured in rat brain cortical membranes by using exogenously supplied substrates. Serotonin, tryptamine, 5-fluorotryptamine and 5-methyltryptamine stimulated PLC with EC50 values of 1.7, 11.2, 15.0, and 29.4 microM, respectively. Maximal PLC stimulation by serotoninergic agonists, which were all equally efficacious, was about 30% of that attained by carbachol. Ketanserin blocked serotoninergic but not cholinergic activation of PLC, whereas, conversely, atropine blocked the latter but not the former response. The rank order of potency for muscarinic agonists was oxotremorine-M greater than pilocarpine = arecoline greater than carbachol = bethanecol. Unlike the case with tissue slices, all of these muscarinic agonists exhibited full efficacy in this assay of PLC stimulation. Activation of PLC by the neurotransmitters or their analogs was dependent on the addition of guanosine 3'-O-thiotriphosphate (GTP gamma S). Stimulation of PLC by GTP gamma S alone or in combination with 5-methyltryptamine had an apparent EC50 of about 0.4 microM. However, when carbachol or other muscarinic agonists were used, the EC50 for GTP gamma S was significantly lower. We have previously shown that dopamine working through D1 receptors inhibits the PLC response to carbachol by preventing this shift in the apparent EC50 for GTP gamma S. Dopamine did not have a similar effect on 5-methyltryptamine stimulation of PLC. The results indicate that the postreceptor mechanisms of PLC activation are distinct for muscarinic as opposed to serotoninergic agonists in brain cortex.
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PMID:Comparison of serotoninergic to muscarinic cholinergic stimulation of phosphoinositide-specific phospholipase C in rat brain cortical membranes. 217 1

Dopamine, like other neurotransmitters, exerts its biological effects by occupation of specific receptor subtypes. The dopamine receptors in the central nervous system and certain endocrine organs are classified into the D1/D2 subtypes. Outside the central nervous system, the dopamine receptors are classified into the DA1/DA2 subtypes. The D1/D2 and DA1/DA2 receptor have marked similarities and some differences, the most notable of which is the lower affinity of the DA dopamine compared with the D dopamine receptor. DA1 receptor activation increases renal blood flow (RBF); stimulation of DA1 and DA2 receptors may also increase glomerular filtration rate (GFR). DA1 agonists inhibit fluid and electrolyte transport indirectly via hemodynamic mechanisms and directly by occupation of DA1 receptors in specific nephron segments. In the proximal tubule, DA1 agonists simulate adenylate cyclase and inhibit Na+-H+ antiport activity. They also increase phospholipase C and inhibit Na+-K+-ATPase activity (presumably as a consequence of protein kinase C activation). The latter effects may be facilitated by DA2 agonists. In cortical collecting ducts, dopamine antagonizes the effects of mineralocorticoids and the hydrosomotic effect of antidiuretic hormone. It has also been suggested that DA1 may also decrease sodium transport by influencing other hormones, such as atrial natriuretic peptide. Studies of dopamine in the young are complicated because of the propensity for dopamine to stimulate alpha-adrenoceptors. Dopamine alone may actually decrease RBF in the perinatal period. In some animals, the renal vasodilatory and natriuretic effects of dopamine increase with age. Renal tubular DA1-stimulated adenylate cyclase activity increases, whereas renal tubular DA1 receptors decrease with age. Renal DA2 receptor density is greater in the fetus; after birth renal DA2 receptors do not change. Endogenous dopamine may regulate sodium excretion in the young differently than in the adult. In the adult, sodium surfeit is associated with an increase in urinary dopamine; the opposite occurs in the young. A decrease in dopamine production or blockade of dopamine receptors results in an antinatriuresis in the adult; dopamine blockade in the young results in a natriuresis. It remains to be determined whether these age-related differences in dopamine effects are due to changes in receptor DA subtype density, second messengers, and/or interaction with other receptors.
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PMID:The dopamine receptor in adult and maturing kidney. 257 2

The effect of dopamine, working through the activation of D2 receptors, on inositol phosphate production induced by thyrotropin-releasing hormone (TRH) was investigated in rat pituitary lactotroph cells. Dopamine (10 microM) did not modify the initial rapid stimulation of inositol 1,4,5-triphosphate and inositol bisphosphate observed within the first 15 s after TRH addition, but progressively inhibited the later inositol phosphate production induced by the neurohormone. This kinetics of inhibition was independent of dopamine preincubation time (from 2 to 10 min). The effect was still visible when dopamine was added after TRH. It was sensitive to pertussis toxin, was unchanged by increasing cellular cAMP levels with 8-Br-cAMP, but was greatly affected by treatments that modify the cytosolic free Ca2+ concentration. Specifically, the dopamine-induced inhibition was prevented by treatment of the cells with the Ca2+ ionophore ionomycin (100-200 nM) and was mimicked either by withdrawal of Ca2+ from the incubation medium or by blockade of voltage-gated Ca2+ channels with verapamil. The dopamine treatment did not decrease the cellular levels of the various phosphoinositides, strongly suggesting that the inhibition of inositol phosphate production is not due to precursor depletion. In isolated membranes, however, dopamine was unable to counteract the inositol phosphate accumulation triggered by TRH. Taken together, the data indicate that inhibition of inositol phosphate production is not a primary event triggered by D2 receptor activation, but is a late consequence, due to the previously demonstrated (Malgaroli, A., Vallar, L., Reza Elahi, F., Pozzan, T., Spada, A., and Meldolesi, J. (1987) J. Biol. Chem. 262, 13920-13927) inhibition by dopamine of the prolonged cytosolic free Ca2+ concentration increase induced by TRH via the activation of voltage-gated Ca2+ channels. These results are inconsistent with the possibility of a direct inhibitory coupling of D2 receptors to phospholipase C in rat pituitary lactotroph cells.
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PMID:Inhibition of inositol phosphate production is a late, Ca2+-dependent effect of D2 dopaminergic receptor activation in rat lactotroph cells. 283 76

The in vitro effect of synthetic diacylglycerol (DG) and phorbol myristate acetate (PMA), potent stimulators of protein kinase C, was studied on prolactin release. These substances increased, in a concentration-dependent manner, prolactin release from primary cultures of anterior pituitary cells. Similarly, exposure of pituitary cells to phospholipase C, which liberates endogenous DG from various substrates, also enhanced prolactin release. The effect of Ca2+ mobilization on PMA-, synthetic DG- or phospholipase C-induced prolactin release was examined. A23187 at 400 nM or 2 ng/ml maitotoxin, a Ca2+ channel activator, did not affect prolactin release by themselves, but enhanced the release of prolactin induced by DG, PMA or phospholipase C. The stimulatory effects of DG, PMA and phospholipase C on prolactin release were reduced by co-incubation with dopamine. These results suggest that the presumed activation of protein kinase C by DG and mobilization of Ca2+ may be synergistically involved in the regulation of prolactin release. Dopamine appears to inhibit prolactin release at a point distal to the DG-enhanced stimulation of the process.
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PMID:Calcium mobilization potentiates prolactin release induced by protein kinase C activators. 315 6

The membrane-permeabilizing effects of streptolysin O, staphylococcal alpha-toxin, and digitonin on cultured rat pheochromocytoma cells were studied. All three agents perturbed the plasma membrane, causing release of intracellular 86Rb+ and uptake of trypan blue. In addition, streptolysin O and digitonin also damaged the membranes of secretory vesicles, including a parallel release of dopamine. In contrast, the effects of alpha-toxin appeared to be strictly confined to the plasma membrane, and no dopamine release was observed with this agent. The exocytotic machinery, however, remained intact and could be triggered by subsequent introduction of micromolar concentrations of Ca2+ into the medium. Dopamine release was entirely Ca2+ specific and occurred independent of the presence or absence of other cations or anions including K+ glutamate, K+ acetate, or Na+ chloride. Ca2+-induced exocytosis did not require the presence of Mg2+-ATP in the medium. The process was insensitive to pH alterations in the range pH 6.6-7.2, and appeared optimal at an osmolarity of 300 mosm/kg. Toxin permeabilization seems to be an excellent method for studying the minimal requirements for exocytosis.
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PMID:Minimal requirements for exocytosis. A study using PC 12 cells permeabilized with staphylococcal alpha-toxin. 404 6

Treatment of striatal washed particles with phospholipase A(2) or C abolished the activation of adenylate cyclase by dopamine but not by N(16)-phenylisopropyl adenosine (PIA). The inhibition of dopamine-sensitive cyclase was dependent on Ca2+ and increased with time and phospholipase concentration. F(-)-sensitive cyclase was not affected by phospholipase A(2) treatment, but was enhanced by phospholipase C treatment. Phospholipase D did not affect basal, PIA, dopamine, or F(-)-sensitive cyclase activities. The observed effects of phospholipase A(2) were not due to either the detergent effect of lysophospholipids or to contaminating proteases. Dopamine-sensitive cyclase, inactivated by pretreatment with phospholipase A(2), was restored by asolectin (a soybean mixed phospholipid), phosphatidylcholine, phosphatidylethanolamine, or phosphatidylserine, but not by phosphatidylinositol. Phosphatidylserine and phosphatidylcholine were equipotent in restoring dopamine-sensitive activity. Lubrol-PX, a nonionic detergent, abolished completely the dopamine-sensitive cyclase activity, whereas PIA-sensitive activity was slightly inhibited. In contrast, digitonin inhibited dopamine- and PIA-sensitive cyclase activity in a parallel fashion. Lubrol-PX released some adenylate cyclase into a 16,000 x g supernatant fraction that was stimulated by PIA but not by dopamine. Removal of most of the free detergent by Bio-bead SM 2 enhanced stimulation by PIA but did not restore sensitive cyclase. The data suggest that the requirement for phospholipids for the coupling of dopamine and adenosine receptors to the striatal adenylate cyclase may be different and that the adenosine receptors may be more tightly coupled to the enzyme than are dopamine receptors.
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PMID:Role of phospholipids in coupling of adenosine and dopamine receptors to striatal adenylate cyclase. 626 36

Dopamine and D1 agonists and NE all increase phosphatidyl inositol-specific phospholipase C (PLC) activity, but whereas dopamine produces a natriuresis, NE has an antinatriuretic effect. To determine if catecholamines differentially regulate the expression of PLC isoforms, we infused fenoldopam, a D1 agonist, or pramipexole, a D1/D2 agonist, intravenously or infused fenoldopam or NE into the renal artery of anesthetized rats. After 3-4 h of infusion, when the expected natriuresis (fenoldopam or pramipexole) or antinatriuresis (NE) occurred, the kidneys were removed for analysis of PLC isoform protein expression activity. Western blot analysis revealed that in renal cortical membranes, fenoldopam and pramipexole increased expression of PLC beta 1 and decreased expression of PLC gamma 1; PLC delta was unchanged. In the cytosol, pramipexole and fenoldopam increased expression of both PLC beta 1 and PLC gamma 1. No effects were noted in the medulla. A preferential D1 antagonist, SKF 83742, which by itself had no effect, blocked the effects of pramipexole, thus confirming the involvement of the D1 receptor. In contrast, NE also increased PLC beta 1 but did not affect PLC gamma 1 protein expression in membranes. The changes in PLC isoform expression were accompanied by similar changes in PLC isoform activity. These studies demonstrate for the first time differential regulation of PLC isoforms by catecholamines.
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PMID:Differential regulation of renal phospholipase C isoforms by catecholamines. 781 30


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