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)

The human dopamine D2L (long form) and D2S (short form) receptors were expressed separately in mouse Ltk- fibroblast cells to investigate whether there is a difference in transmembrane signaling of these D2 receptors. Both receptors induced two signals, a phosphatidylinositol-linked mobilization of intracellular calcium and an inhibition of cyclic adenosine 3'-5' monophosphate (cAMP) accumulation, each with similar response magnitudes and identical pharmacology. Both calcium and cAMP signals were sensitive to pretreatment with pertussis toxin (PTX), indicating mediation by coupling to Gi/Go proteins. However, the two forms of D2 receptor were distinguished by acute prior activation of protein kinase C (PKC) with 12-O-tetradecanoyl 4 beta-phorbol 13-acetate (TPA): TPA blocked the D2S-mediated increase in cytosolic free calcium concentration ([Ca2+]i) in a concentration-dependent manner (between 10 nM and 1 microM), whereas the D2L receptor-induced increase in [Ca2+]i was resistant to TPA and was only partially (60%) inhibited by 100 microM TPA. By contrast, TPA did not alter the inhibition of cAMP accumulation induced by activation of either D2S or D2L receptors. We conclude that, in the L cell system, prior activation of PKC differentially modulates the transmembrane signaling of the D2L and D2S receptors, preferentially inhibiting the D2S receptor-mediated calcium signal but not altering the dopamine-induced inhibitory cAMP signal of either receptor subtype.
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PMID:Differential sensitivity of the short and long human dopamine D2 receptor subtypes to protein kinase C. 133 29

A microphysiometer was used to quantify the rate of extracellular acidification by C6 glioma cells and L fibroblasts expressing recombinant dopamine D2 receptors. The dopamine D2 receptor agonist, quinpirole, accelerated the rate of acidification of the medium by C6 cells expressing either the short or long form of D2 receptors, D2(415) and D2(444), but not by wild-type cells that were not transfected with a D2 receptor cDNA. The rate of acidification increased with increasing concentrations of quinpirole up to 100 nM. Inhibition of the response by the dopamine D2 antagonist, spiperone, provided additional evidence that the enhanced extracellular acidification resulted from stimulation of D2 receptors. To test the hypothesis that D2 receptor-stimulated extracellular acidification was due to transport of protons by a Na+/H+ antiporter and reflected intracellular alkalinization, the effect of two inhibitors of Na+/H+ exchange, amiloride and methyl-isobutyl-amiloride, was determined. Both compounds inhibited quinpirole-induced extracellular acidification at concentrations that did not alter D2 receptor-mediated inhibition of adenylylcyclase or radioligand binding to D2 receptors. In addition, quinpirole-induced extracellular acidification was greatly inhibited by removal of sodium from the extracellular medium, confirming the participation of Na+/H+ exchange in the extrusion of acid. Quinpirole (100 nM) also increased the rate of extracellular acidification by L cells expressing D2(415), LZR1 cells. Treatment with pertussis toxin (100 ng/ml for 18 h) had no effect on the quinpirole-induced acid extrusion by C6D2(415) and LZR1 cells, although the same pertussis toxin treatment regimen completely prevented inhibition of adenylylcyclase. We conclude that recombinant D2 receptors accelerate Na+/H+ exchange in C6 cells and L fibroblasts by a pathway that does not involve inhibition of adenylylcyclase or pertussis toxin-sensitive G proteins.
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PMID:Dopamine D2 receptor stimulation of Na+/H+ exchange assessed by quantification of extracellular acidification. 136 Nov 88

Substance P (SP) stimulates polyphosphoinositide breakdown in the rat anterior pituitary through an NK-1 receptor. In the present study we present evidence that the coupling between the SP-NK1 receptor complex and polyphosphoinositide-specific phospholipase C (PI-PLC) in rat anterior pituitary membranes may involve a mechanism consistent with a GTP-binding protein. The formation of inositol phosphates from [3H]myo-inositol-labelled anterior pituitary membranes induced by SP was potentiated by GTP and non-hydrolysable guanine nucleotides. The stimulatory effects of SP alone and SP plus GTP could be blocked by addition of GDP-beta-S (guanosine 5-O-(thiodiphosphate] in excess. Basal and SP plus guanine nucleotide-induced inositol phosphate formation were stimulated by fluoride, whereas the effect of SP alone was inhibited. Pretreatment of anterior pituitary membranes with sodium deoxycholate attenuated the inositol phosphate response elicited by GTP and GTP-gamma-S, whereas basal and SP-stimulated inositol phosphate production showed a peak at 1 mg sodium deoxycholate/ml. SP, fluoride and guanine nucleotide stimulatory effects on hydrolysis of polyphosphoinositide (PPI) were unaffected by pretreatment of anterior pituitary cells with cholera or pertussis toxin for 12h. Treatment of anterior pituitary membranes with cholera and pertussis toxin yielded [32P]ADP-ribosylation of two proteins with molecular masses of 45 and 41 kDa respectively. We conclude that SP coupling to PI-PLC through the NK1 receptor in the rat anterior pituitary involves a GTP-binding mechanism distinct from the G-proteins associated with adenylate cyclase, Gs and Gi.
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PMID:Substance P stimulation of polyphosphoinositide hydrolysis in rat anterior pituitary membranes involves a GTP-dependent mechanism. 171 80

Substance P excites neurons by suppressing inward rectification channels. We have investigated whether the substance P receptor interacts with the inward rectification channels through a guanine nucleotide-binding protein (G protein) by using dissociated cultured neurons from the nucleus basalis of newborn rats. During intracellular application of guanosine 5'-[gamma-thio]triphosphate and 5'-guanylyl imidodiphosphate, hydrolysis-resistant GTP analogues that irreversibly stimulate G proteins, substance P application almost irreversibly suppressed the inward rectification channels. Pretreatment with pertussis toxin did not significantly influence substance P action. Intracellular application of cAMP and 3-isobutyl-1-methylxanthine or of 9-(tetrahydro-2-furyl)adenine (SQ 22,536), an inhibitor of adenylate cyclase, did not alter the substance P-induced response. We conclude that the inhibition of inward rectification channels by substance P is mediated through a G protein. However, the effect is not mediated through adenylate cyclase or the cAMP system. This G protein, which is insensitive to pertussis toxin, could be an unidentified G protein.
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PMID:Pertussis toxin-insensitive G protein mediates substance P-induced inhibition of potassium channels in brain neurons. 245 66

The D2 dopamine agonist, bromocriptine, has been used as treatment for human PRL-secreting pituitary adenomas. The result of bromocriptine treatment is often a substantial reduction of tumor mass, suggesting that the dopamine agonist is acting as an antiproliferative agent. This action can be observed with a clonal pituitary tumor cell line. The agonist activation of the D2 dopamine receptor inhibits the growth of GH4ZR7 cells, a GH4C1 cell line stably transfected with the cDNA encoding the short form of the D2 dopamine receptor. This effect of dopamine was not sensitive to overnight treatment with 100 ng/ml pertussis toxin. Treatment of GH4ZR7 cells with the phorbol ester 4 beta-phorbol 12,13-didecanoate resulted in the loss of dopaminergic inhibition of growth, whereas treatment with 4 alpha-phorbol 12,13-didecanoate had no effect. Inhibitors of protein kinase-C (PKC), such as staurosporine and H7, also blocked the effect of dopamine. Down-regulation of cellular PKC by phorbol ester treatment resulted in a complete loss of dopaminergic inhibition of growth. Long term treatment of GH4ZR7 cells with TRH results in a specific down-regulation of the epsilon form of PKC and abolished the ability of dopamine to inhibit growth. These results suggest that PKC epsilon is involved in mediating the antiproliferative effects of dopamine. This mediation of growth appears to be through a novel signaling pathway for the D2 dopamine receptor.
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PMID:The D2 dopamine receptor mediates inhibition of growth in GH4ZR7 cells: involvement of protein kinase-C epsilon. 750 37

Site-directed mutations of the cDNA for Gi1 alpha, Gi21 alpha, and Gi3 alpha were constructed which changed the cysteine residue at the C terminus to a glycine residue (Gi alpha PT). This mutation of the Gi alpha would not permit the subsequent covalent modification by pertussis toxin, which requires the cysteine moiety. The cDNA for each of the mutant Gi alpha subunits was transfected into GH4C1 cells with either of the alternative splice forms of the D2 dopamine receptor and clonal lines were generated. After treatment with pertussis toxin to remove the contribution from endogenous Gi proteins, the receptor-mediated inhibition of adenylyl cyclase was examined. The D2 dopamine receptor, short form (D2s) signaled through the Gi2 alpha PT mutant in these cells with an affinity for agonist which was comparable to that observed in cells transfected with the cDNA for D2s alone or the signaling observed in the absence of pertussis toxin. The long form of the D2 dopamine receptor (D2l) signaled through the Gi3 alpha PT mutant to inhibit forskolin-stimulated adenylyl cyclase, with an affinity for agonist comparable to that observed in cells transfected with the cDNA for D2l alone. The receptor for somatostatin (somatotropin release inhibiting factor) was used as an endogenous control receptor in these cell lines. The somatotropin release inhibiting factor was able to signal through both Gi1 alpha PT and Gi3 alpha PT to inhibit forskolin-stimulated adenylyl cyclase. These results indicated that receptors use distinct Gi proteins to signal to a common effector.
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PMID:The D2 dopamine receptor isoforms signal through distinct Gi alpha proteins to inhibit adenylyl cyclase. A study with site-directed mutant Gi alpha proteins. 791 15

The D2 dopamine receptor expressed in the MMQ cell line was characterized by saturation binding using the D2 dopamine radioligand [3H]spiperone. The KD for spiperone was 41 pM and the Bmax for these sites was 34 fmol/mg protein. Inhibition of forskolin-stimulated cAMP accumulation occurred in response to a variety of D2 agonists, and the agonist effects were reversed by D2 antagonists. Pertussis toxin pretreatment abolished agonist inhibition of cAMP accumulation. In addition, the alpha 2-adrenergic agonist UK 14304 inhibited cAMP accumulation; this effect was reversed by an alpha 2-adrenergic antagonist but not by a D2 antagonist, indicating the presence of alpha 2-adrenergic receptors on these cells. Specific oligonucleotide primers were used in the polymerase chain reaction to determine, by restriction enzyme analysis and Southern blotting, that the long form of the two alternatively spliced variants of the D2 dopamine receptor was the predominant variant expressed in these cells.
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PMID:Further characterization of the D2 dopamine receptor expressed in MMQ cells. 810 26

cDNAs coding for three types of alpha-subunits of GTP-binding proteins Gs and G0 (a short form of alpha s with Asp-Ser in positions 71 and 72, a long form of alpha s with the insertion of 16 amino acid residues instead of Asp-Ser (71-72)--both from bovine brain, and alpha 0 from bovine cerebellum as well as some chimeric alpha s/alpha 0 genes were cloned into a modified pGEM-2 plasmid vector under the control of the SP6 promoter. All the genes were in vitro transcribed and translated, and some functional properties of the resulting proteins were determined, such as adenylyl cyclase activation, ADP-ribosylation with pertussis toxin, limited nucleotide-dependent trypsin proteolysis. Parts of the alpha s polypeptide chain necessary for the activation of adenylyl cyclase were mapped. The alpha s domain interacting with adenylyl cyclase is formed by the alpha s polypeptide chain fragments 235-294 and 337-356 (numbering as of the alpha s long form).
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PMID:[Localization of segments in the Gs protein interacting with adenylate cyclase using a Gs/G0-chimera]. 811 36

The presence of G-proteins in highly purified fractions from frog and rabbit skeletal muscles was analyzed by Bordetella pertussis toxin-catalyzed ADP-ribosylation and by immunoblots. Two B. pertussis toxin substrates were present in transverse tubules and sarcoplasmic reticulum from frog and rabbit skeletal muscle. Immunoblot analysis suggested that the two B. pertussis toxin substrates present in rabbit sarcoplasmic reticulum are possibly alpha i2 and alpha i3, but the corresponding substrates in sarcoplasmic reticulum from frog are still unidentified. Transverse tubules isolated from both rabbit and frog also contained alpha i2 and alpha i3; additionally, beta 35, beta 36, alpha o (weak immunoreactivity), alpha i1 (and/or alpha i3 in frog), alpha s (short form only in frog), and alpha q were found. Sarcoplasmic reticulum from rabbit also contained alpha s (predominantly alpha s short), beta 36, and alpha q. The presence of alpha q in sarcoplasmic reticulum, in addition to transverse tubules, is potentially a very important finding since this G-protein has been described only in plasma membranes so far. Also, this study describes the candidate G-proteins for the control of excitation-contraction coupling in skeletal muscle.
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PMID:Characterization and subcellular distribution of G-proteins in highly purified skeletal muscle fractions from rabbit and frog. 816 Dec 24

Previously, we showed that both D2 and D4 dopamine receptors inhibited adenylate cyclase in a pertussis toxin (Ptx)-sensitive manner in the dopamine-producing MN9D cell line, whereas only D2 receptors did so in a fibroblast cell line, CCL1.3. Of the known Ptx-sensitive G proteins, MN9D cells expressed G alpha i2, G alpha oA and G alpha oB, whereas CCL1.3 cells expressed only G alpha i2. Here we cotransfected MN9D and CCL1.3 cells with either the long form of the D2 receptor (D2L) or the D4 receptor and a mutant Ptx-resistant G protein alpha-subunit. When cotransfected CCL1.3 cell lines were tested for the ability of Ptx to block receptor-mediated inhibition of cyclic AMP accumulation, D2 receptors were found to couple to mutant G alpha i2 and G alpha i3 but not G alpha i1 or G alpha oA. D2 also coupled to mutant G alpha i2 but not G alpha oA in MN9D cells. In contrast, D4 receptors did not couple to either mutant G alpha i2 or G alpha oA subunits in MN9D cells. These data suggest that D4 receptor-mediated inhibition of adenylate cyclase is not coupled via the same mechanisms used by D2 receptors. D2L receptors are capable of coupling to more than one G protein in the modulation of cyclic AMP.
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PMID:Dopamine D2L receptor couples to G alpha i2 and G alpha i3 but not G alpha i1, leading to the inhibition of adenylate cyclase in transfected cell lines. 876 70


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