Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 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 (DA) has dual actions (inhibitory and stimulatory) in the regulation of prolactin (PRL) release, depending on its concentration. To investigate the stimulatory effects of DA, perifused rat anterior pituitary cells were exposed to the highly-specific DA D2 receptor agonist, quinpirole hydrochloride (LY). Very low concentrations of LY (10(-12)-10(-10) M) stimulated PRL release and potentiated thyrotropin-releasing hormone (TRH)-induced PRL release. Higher concentrations of LY did not stimulate. Pretreatment with pertussis toxin (30 ng/ml, 24 h) completely abolished these effects of LY. The D2 receptor antagonist, metoclopramide, also blocked the potentiation by LY of TRH-induced PRL release. These data indicate that very low concentrations of dopamine stimulate PRL release via an interaction with a D2 receptor connected to a pertussis toxin-sensitive G protein.
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PMID:Stimulatory effects of quinpirole hydrochloride, D2-dopamine receptor agonist, at low concentrations on prolactin release in female rats in vitro. 135 55

Dopaminergic D2 receptor agonists, such as bromocriptine, are potent anti-proliferative agents in the treatment of human pituitary adenomas. We have reproduced the anti-proliferative effect of dopamine in an established pituitary cell line stably transfected with the rat D2 dopamine receptor cDNA. We found that dopaminergic inhibition of DNA synthesis parallels the stimulation of a phosphotyrosine phosphatase activity. Both actions are blocked by pertussis toxin and by the phosphotyrosine phosphatase inhibitor, vanadate. We suggest that the anti-proliferative action of dopamine is mediated, at least in part, by the dopaminergic stimulation of a phosphotyrosine phosphatase.
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PMID:Dopaminergic inhibition of DNA synthesis in pituitary tumor cells is associated with phosphotyrosine phosphatase activity. 136 8

Y-79 human retinoblastoma cells can be induced to express significant quantities of functional D2 dopamine receptors after attachment and differentiation with sodium butyrate. In membranes prepared from differentiated Y-79 cells, the D2 dopaminergic antagonist [3H] methylspiperone exhibits a KD of 77 pm and a Bmax of 60 fmol/mg of protein, whereas the antagonist [125I]iodosulpride reveals a KD of 0.77 nM and a Bmax of 40 fmol/mg of protein. Dopamine also induces a pharmacologically specific, pertussis toxin-sensitive, dose-dependent inhibition of forskolin-stimulated adenylyl cyclase activity, with an EC50 of 2 microM and a maximal response at 100 microM (approximately 50% enzyme inhibition). Pretreatment of the cells with dopamine results in a diminution in the subsequent ability of dopamine to inhibit adenylyl cyclase activity. This effect is time dependent, reaching maximal desensitization after approximately 24 hr. The dopamine dose-response curve for inducing desensitization exhibits an EC50 of approximately 2-3 microM and a maximal response at approximately 0.1-1 mM, similar to that for inhibiting adenylyl cyclase activity. After maximal desensitization, the EC50 for dopamine-induced inhibition of adenylyl cyclase activity is increased greater than 20 fold (lower affinity) and the maximum inhibition is decreased to approximately 15%, representing an approximately 70% desensitization. The agonist-induced desensitization is pharmacologically specific, inasmuch as preincubation of the cells with the dopaminergic agonists epinine and (+-)-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene or the D2-selective agonist N-0434 also results in desensitization of dopamine-induced inhibition of enzyme activity, whereas preincubation with the D1-selective agonist SKF-38393 or with the nondopaminergic agonists isoproterenol and serotonin results in little or no desensitization. Preincubation of the cells with dopamine also promotes a time-dependent increase (approximately 3-fold) in the KD for [3H]methylspiperone, with no change in its Bmax. In contrast, after dopamine preincubation, the KD for [125I]iodosulpride is unchanged, whereas its Bmax is reduced by approximately 50% upon maximum desensitization. In addition, agonist pretreatment promotes a functional uncoupling of the D2 receptor, as suggested by a loss of high affinity agonist binding observed in radioligand competition binding assays after desensitization. Upon removal of agonist, the cellular D2 receptor binding activity and functional response recover to control levels within a 24-hr period. These results suggest that prolonged exposure of cells to dopaminergic agonists initiates a desensitization process involving a functional uncoupling of the D2 dopamine receptor as well as a loss of its ligand binding activity.
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PMID:Agonist-induced desensitization of D2 dopamine receptors in human Y-79 retinoblastoma cells. 167 85

The regulation of cellular responsiveness to dopamine via the D2 dopamine receptor was investigated in mouse fibroblast Ltk-cells stably expressing the rat D2-short receptor [Nature (Lond.) 336:783-787 (1988)]. Dopamine inhibited forskolin-stimulated cAMP levels in these cells (half-maximal inhibition at 3.9 +/- 1.1 nM), and the inhibition by dopamine was blocked by D2 antagonists and was pertussis toxin sensitive. Treatment of these cells with the D2 agonist quinpirole (1 microM) resulted in desensitization of dopaminergic inhibition of forskolin-stimulated cAMP accumulation, with a approximately 4-fold decrease in the potency of dopamine after 1 hr of treatment. No significant changes in total cellular D2 receptor concentrations were observed, even after prolonged agonist treatment. At longer time points, basal and forskolin-stimulated cellular cAMP levels were increased in treated cells. The effect of D2 agonist treatment on membrane adenylyl cyclase (EC 4.6.1.1) activity was examined. Basal and forskolin- and prostaglandin E1-stimulated adenylyl cyclase activities were increased by quinpirole treatment for 24 hr. This sensitization of adenylyl cyclase was blocked by the presence of a D2 antagonist. Pertussis toxin pretreatment blocked the sensitization of adenylyl cyclase by quinpirole, although pertussis toxin also caused increased adenylyl cyclase activity on its own. Sensitization was not dependent upon dopaminergic inhibition of intracellular cAMP levels, because quinpirole treatment in the presence of membrane-permeable cAMP analogs or 3-isobutyl-1-methylxanthine (an inhibitor of cAMP phosphodiesterase) resulted in greater sensitization of adenylyl cyclase activity than quinpirole treatment alone. These results suggest that, in this model system, responsiveness to dopamine via the D2 receptor is regulated by both desensitization of receptor function and sensitization of the stimulatory adenylyl cyclase pathway.
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PMID:Regulation of responsiveness at D2 dopamine receptors by receptor desensitization and adenylyl cyclase sensitization. 184 20

We have previously shown that dopamine-evoked inhibition of corticosteroid production from adrenocortical cells is mediated through a decrease in prostaglandin biosynthesis. Since the catecholamine did not alter the stimulatory effect of arachidonic acid, it was proposed that dopamine may inhibit the formation of arachidonate from glycerophospholipids. To test this hypothesis, the effect of dopamine on phosphoinositol lipid metabolism was investigated in frog interrenal (adrenal) tissue. In [3H]myo-inositol-prelabeled frog interrenal slices, a short pulse of dopamine (50 microM) induced a biphasic effect on inositol phosphate production: a transient (1-min) increase, followed by a sustained inhibition. Concurrently, dopamine induced a transient reduction followed by a sustained increase in polyphosphoinositides. A 10-min pulse of the D2 dopamine receptor agonist apomorphine (50 microM) elicited a significant inhibition of basal levels of inositol phosphates (tris-, bis-, and mono-), and an increase in plasma membrane phosphoinositol lipid contents. The inhibitory effect of dopamine on inositol phosphate formation and corticosteroid release was abolished by a 24-h incubation of interrenal slices with pertussis toxin. In [3H]arachidonic acid-prelabeled interrenal slices, dopamine also decreased diacylglycerol (DG) and arachidonic acid (AA) concentrations. A delay of 1 min was observed between inhibition of DG and arachidonate, suggesting that AA is probably generated from DG. We conclude that in the adrenal cortex, activation of dopamine D2 receptors is coupled to a phosphoinositide-specific phospholipase-C mediated via a pertussis toxin-sensitive G-protein. Taken together, our data indicate that inhibition of inositol phosphate and AA formation is one of the mechanisms by which dopamine controls corticosteroid production by adrenocortical cells.
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PMID:Dopamine inhibits inositol phosphate production, arachidonic acid formation, and corticosteroid release by frog adrenal gland through a pertussis toxin-sensitive G-protein. 190 70

The selectivity of D2 dopamine receptor-guanine nucleotide-binding protein (G protein) coupling was studied by reconstitution techniques utilizing purified D2 dopamine receptors from bovine anterior pituitary and resolved G proteins from bovine brain, bovine pituitary, and human erythrocyte. Titration of a fixed receptor concentration with varying G protein concentrations revealed two aspects of receptor-G protein coupling. First, Gi2 appeared to couple selectively with the D2 receptor with approximately 10-fold higher affinity than any other tested Gi subtype. Second, the G proteins differed in the maximal receptor-mediated agonist stimulation of the intrinsic GTPase activity. Gi2 appeared to be maximally stimulated by agonist-receptor complex with turnover numbers of approximately 2 min-1. The other Gi subtypes, Gi1 and Gi3, could be only partially activated, resulting in maximal rates of GTPase of approximately 1 min-1. Agonist-stimulated GTPase activity was not detected in preparations containing Go from bovine brain. The differences in maximal agonist-stimulated GTPase rates observed among the Gi subtypes could be explained by differences in agonist-promoted guanyl nucleotide exchange. Both guanosine 5'-3-O-(thio)triphosphate (GTP gamma S) binding and GDP release parameters were enhanced 2-fold for the Gi2 subtype over the other Gi subtypes. These results suggest that even though several types of pertussis toxin substrate may exist in most tissues, a receptor may interact discretely with G proteins, thereby dictating signal transduction mechanisms.
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PMID:Specificity of receptor-G protein interactions. Discrimination of Gi subtypes by the D2 dopamine receptor in a reconstituted system. 213 24

In primary culture of anterior pituitary cells, BAY-K-8644, a calcium channel agonist, stimulated PRL secretion by 83% with EC50 of 18 nM. This effect was blocked by nifedipine, a calcium channel antagonist. The stimulations of PRL secretion induced by potassium (50 mM) and BAY-K-8644 were additive. Dopamine inhibited basal as well as BAY-K-8644-stimulated PRL secretion by 64% and 75%, respectively, and with respective EC50 values of 4.5 and 0.6 nM. In the presence of 50 mM K+, dopamine only partially blocks the dose-dependent stimulation of PRL secretion induced by the calcium channel agonist. The inhibitory dopamine effect was blocked by (+)butaclamol, a specific dopamine receptor antagonist. The dopamine response was also blocked by 1-sulpiride, a specific dopamine D2 receptor antagonist, and mimicked by RU 24926, a specific dopamine D2 receptor agonist, suggesting that the dopamine effect on BAY-K-8644-stimulated PRL secretion was mediated through a D2 dopamine receptor. Although unknown, the mechanism by which dopamine inhibited the BAY-K-8644-stimulated PRL secretion involves a GTP binding protein sensitive to Bordetella pertussis toxin. In fact, the dopamine inhibition of PRL secretion induced by the calcium channel agonist was blocked by the pretreatment of cells with the toxin. These results suggest that dopamine D2 receptors in lactotroph cells modulate calcium influx through a GTP binding protein.
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PMID:Dopamine inhibits prolactin secretion stimulated by the calcium channel agonist Bay-K-8644 through a pertussis toxin-sensitive G protein in anterior pituitary cells. 245 6

The ligand binding subunit of the D2 dopamine receptor (Mr approximately equal to 94,000) can be visualized by autoradiography following photoaffinity labeling with [125I]N-azidophenethylspiperone and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Following removal of sialic acids with the exoglycosidase, neuraminidase, [125I]N-azidophenethylspiperone photoincorporated into a protein of Mr = 54,000 with the appropriate pharmacological profile for D2 receptors. The desialylated D2 receptor bound dopaminergic agonists with high affinity and was capable of coupling to a functional G-protein as indexed by: 1) pertussis-toxin mediated [32P]ADP ribosylation of proteins of Mr = 42,000 and 39,000, and 2) the conversion of the agonist high affinity form of D2 receptors to one displaying low affinity for agonists in the presence of guanine nucleotides. These data suggest that sialic acid residues do not contribute significantly to the ligand binding characteristics of D2 receptors despite the large change produced in the estimated molecular mass of the binding subunit.
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PMID:Dopamine D2 receptors retain agonist high-affinity form and guanine nucleotide sensitivity after removal of sialic acid. 290 37

When the crude synaptic membrane preparations from bovine striatum were treated with islet-activating protein (IAP), one of the pertussis toxins, a protein with a molecular weight of about 40,000 was ADP-ribosylated. In parallel with this ADP-ribosylation, there was a decrease in D2 dopamine receptor affinity for agonist, while the affinity for antagonist remained unaltered. Addition of GTP to nontreated membranes also resulted in a decrease in the affinity of D2 receptor for agonist, and there was no further reduction of affinity for agonist with addition of GTP to the IAP-treated membranes. As IAP specifically acts on the guanine nucleotide regulatory protein which mediates the inhibition of adenylate cyclase activity (Ni), our findings indicate a possible molecular interaction between the brain D2 dopamine receptor and Ni.
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PMID:Selective decrease in the affinity of D2 dopamine receptor for agonist induced by islet-activating protein, pertussis toxin, associated with ADP-ribosylation of the specific membrane protein of bovine striatum. 622 33


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