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)

In T-cells, the Shaker-related gene, Kv1.3 encodes the type n K+ channel, whereas the type l channel is a product of the Shaw. subfamily gene, Kv3.1. Both these genes are also expressed in the brain. We have used the Xenopus oocyte heterologous expression system to study the modulatory effects of serotonin (5-hydroxytryptamine, 5-HT) on both these cloned channels. In oocytes coexpressing the mouse 5-HT1c receptor and mouse Kv1.3 channel, addition of 100 nM 5-HT causes a complete and sustained suppression of Kv1.3 currents in approximately 20 min. In contrast, 5-HT has no effect on mouse Kv3.1 currents when coexpressed with 5-HT1c receptor. The 5-HT-mediated suppression of Kv1.3 currents proceeds via activation of a pertussis toxin-sensitive G protein and a subsequent rise in intracellular Ca2+, but Ca2+ does not directly block the channel. Protein kinase (PK) C activation is not part of the pathway linking 5-HT1c receptor to Kv1.3 channels. However, phorbol esters independently suppress Kv1.3 currents. Deletion of the first 146 amino acids from the NH2-terminal, containing putative tyrosine kinase and PKA phosphorylation sites, does not alter the time course of 5-HT-mediated suppression of Kv1.3 currents, indicating that these residues are not necessary for modulation. Treatment of oocytes with calmodulin or phosphatase inhibitors does not alter 5-HT-mediated modulation. Collectively, these experiments indicate that the mouse Kv1.3 channel is capable of being modulated by 5-HT via 5-HT1c receptor in a G protein and Ca(2+)-dependent manner, but the subsequent steps in the pathway remain elusive.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Full-length and truncated Kv1.3 K+ channels are modulated by 5-HT1c receptor activation and independently by PKC. 750 90

We have previously reported that the calciotropic hormone 1,25(OH)2-vitamin D3 stimulates influx of Ca2+ into cultured rat and embryonic chick myoblasts via voltage sensitive Ca(2+)-channels. In the present study, we show that this effect of 1,25(OH)2D3 requires the mediation of the adenylylcyclase signalling system since the hormone-dependent Ca2+ influx is abolished by specific inhibitors of adenylylcyclase and protein kinase A and mimicked by forskolin and dibutyryl cAMP. 1,25(OH)2D3-stimulated elevations in cellular cAMP paralleled increases in Ca2+ uptake, further suggesting a coupling of adenylylcyclase activation and calcium influx. Fluoride and GTP gamma S mimicked 1,25(OH)2D3-stimulation of calcium influx while GDP beta S suppressed the effect of the hormone. Cholera toxin and Bordetella pertussis toxin both increased 45Ca2+ uptake in rat and chick myoblasts. The hormone further increased cholera toxin actions, but was unable to modify pertussis toxin-induced 45Ca2+ uptake, suggesting a similar target of action for pertussis toxin and 1,25(OH)2D3. Incubation of microsomal membranes with the sterol (10 nM, 2 min) markedly displaces (-32%) [35S]GTP gamma S binding to the membranes. ADP-ribosylation of the pertussis toxin-sensitive 41 kDa substrate was significantly increased (+40%) in 1,25(OH)2D3-pretreated cells. These results suggest that 1,25(OH)2D3-stimulated influx of Ca2+ into rat and embryonic chick cultured myoblasts sequentially requires inhibition of a pertussis toxin-sensitive G protein, accumulation of cAMP and activation of dihydropyridine-sensitive Ca(2+)-channels through PKA-mediated phosphorylation events.
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PMID:Modulation by 1,25(OH)2-vitamin D3 of the adenylyl cyclase/cyclic AMP pathway in rat and chick myoblasts. 757 77

1. The G protein-mediated coupling of a somatostatin (somatotropin-releasing inhibitory factor; SRIF) receptor to the ATP-dependent K+ channel (K+ATP channel) has been studied in insulin-secreting cells using the patch clamp technique. 2. In excised outside-out patches, the concentration-dependent stimulation of the K+ATP channel by SRIF was biphasic. Stimulation reached a maximum at 15 nM (EC50 = 5.5 nM), then decayed to a minimum at 50 nM and returned to maximum stimulation at 500 nM. 3. In cell-attached patches, bath-applied SRIF caused K+ATP channel stimulation in most experiments. In a few cases, however, SRIF suppressed channel activity, a response that was reversed by addition of dibutyryl cyclic AMP (DBcAMP). Channel stimulation by SRIF or by DBcAMP did not occur in the presence of glucose. 4. In excised inside-out patches, the alpha-subunits of Gi or G(o)-type G proteins stimulated the K+ATP channel (EC50 = 29 and 42 pM, respectively). The K+ATP channel stimulation by alpha i- or alpha o-subunits had no effect on the concentration-dependent inhibition by ATP. 5. In excised inside-out patches, K+ATP channel activity was reduced by inhibitors of protein kinase C (PKC) and stimulated by a PKC activator. The stimulatory effect of PKC was unaffected by the presence of pertussis toxin, but stimulation by exogenous alpha-subunits of the G protein Gi or G(o) was prevented by PKC inhibitors. 6. From these data we deduce that SRIF can affect K+ATP channel activity directly via a membrane-delimited pathway or indirectly via a pathway requiring diffusible messengers. In the former case, alpha i/alpha o may either enhance PLC activity, stimulating PKC and thus inducing K+ATP channel phosphorylation with consequent increase of activity, or channel phosphorylation by PKC may facilitate a direct stimulation of the channel by alpha i/alpha o. In the latter case, an alpha i/alpha o-induced fall in cAMP contributes to reduced PKA-mediated phosphorylation and suppression of channel activity.
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PMID:Characterization of the G protein coupling of a somatostatin receptor to the K+ATP channel in insulin-secreting mammalian HIT and RIN cell lines. 765 84

The effects of endothelin-1 (ET-1) on whole-cell cardiac PKA-dependent Cl- currents (ICl) were investigated using patch clamp techniques. ET-1 inhibited the isoproterenol-induced ICl with a half-maximally effective concentration of approximately 1 nM. ET-1 also inhibited the forskolin-induced current in a similar concentration range. The effects of ET-1 were abolished by pre-treatment of the cells with pertussis toxin. Since ET-1 was ineffective at inhibiting the ICl induced by internal dialysis with cyclic AMP, it is unlikely that the Gi-protein had a direct effect on channel gating or phosphorylation of the channel by PKA. It is concluded that ET-1 inhibited the cardiac PKA-dependent ICl by attenuating activation of adenylate cyclase and that this effect was mediated by a pertussis toxin-sensitive G-protein, presumably Gi.
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PMID:The effects of endothelin-1 on the PKA-dependent Cl- current in the heart. 775 29

Phosphorylation, protein carboxyl methylation, and ADP-ribosylation were assayed in renal basolateral membranes and brush border membranes isolated from rats treated by subcutaneous administration of 5 or 10 mg/(kg.day) of cyclosporin A (CsA) for 10 days to investigate potential alterations in signal transduction in kidney cortex. Protein carboxyl methylation of class II measured in membranes and in cytosolic fraction was not affected by CsA treatment. ADP-ribosylation performed in the presence of pertussis or cholera toxin was also similar in control and treated rats. However, changes in phosphorylation of endogenous substrates were observed in membranes and cytosol isolated from rats treated with 10 mg/(kg.day) of CsA. Phosphorylation was increased for two brush border membrane proteins (56 and 77 kilodaltons (kDa)) by 47 and 24% and for two basolateral membrane proteins (51 and 80 kDa) by 28 and 29%, respectively. In the cytosolic fraction, phosphorylation of two proteins (31 and 65 kDa) was increased by 37% and that of 25- and 43-kDa proteins was reduced by 29%. Protein kinase A, protein kinase C, and tyrosine protein kinase activities were also determined in membranes. Increases in protein kinase C and tyrosine protein kinase activities were observed in basolateral membranes, but not in brush border membranes after cyclosporin A administration. Endogenous substrates for tyrosine kinase were also detected with an antiphosphotyrosine (PY20) monoclonal antibody. Densitometric analysis indicated that the phosphorylation of three proteins of high molecular masses (61, 132, and 183 kDa) was stimulated by CsA in basolateral membranes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cyclosporin treatment alters protein phosphorylation in kidney membranes. 781 48

The signal transduction of TSH in invasion and growth of FTC 133, a human follicular thyroid cancer cell line, was investigated. TSH (0.01-1 mIU/ml) stimulated invasion of FTC 133 by 21% and growth by 20% of basal. Cyclic AMP-stimulators and inhibitors had no effect at any concentration. The PKC-agonist TPA enhanced invasion and growth by 15%, whereas staurosporine, a PKC-antagonist, inhibited them by 32% and 60%, respectively. The latter also reversed TSH stimulation. EGF enhanced invasion (42%) and growth of FTC 133 (25%). Staurosporine did not reverse EGF stimulation. The tyrosine kinase antagonist genistein reversed EGF, but not TSH stimulation. Pertussis toxin inhibited invasion (18%) and growth (22%). Cholera toxin was less inhibitive. We demonstrated for the first time, that TSH stimulates invasion and growth of human thyroid cancer cells in vitro by PKC- rather than PKA-stimulation.
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PMID:Thyrotropin stimulates invasion and growth of follicular thyroid cancer cells via PKC- rather than PKA-activation. 821 54

The present study assesses the relationship between G-proteins and protein kinase-C (PKC) in the gonadotrope. Cells were depleted of PKC with 1 microM phorbol 12-myristate 13-acetate for 12 h, followed by medium 199-BSA for 6 h before treatment with vehicle, pertussis toxin (PTX), cholera toxin (CTX), or (Bu)2cAMP (dBcAMP) for 18 h. PTX (10 ng/ml) significantly decreased GnRH-stimulated inositol phosphate (IP) production over a range of 10(-8)-10(-6) M GnRH. The degree of this inhibition was the same in control cells and PKC-depleted cells. Pretreatment with CTX (0.5 microgram/ml) significantly decreased GnRH-stimulated IP production over a range of 10(-9)-10(-6) M GnRH in PKC-depleted cells. This effect was mimicked by pretreatment with 3 mM dBcAMP. Although CTX and dBcAMP both decreased GnRH-stimulated IP production in control cells, this effect was enhanced in PKC-depleted cells. CTX (0.1 microgram/ml) and dBcAMP (3 mM) both enhanced GnRH-stimulated LH release, whereas PTX (100 ng/ml) had no effect. This was observed in control as well as PKC-depleted cells. Both PKA and PKC are capable of regulating IP turnover by phosphorylating phospholipase-C at distinct sites. CTX activates a G-protein that increases cAMP. cAMP can then activate PKA. In PKC-depleted cells, CTX inhibits GnRH-stimulated IP production. This effect is mimicked by dBcAMP, which suggests a role for PKA in the gonadotrope. The results of this study provide evidence for cross-talk between a CTX-sensitive G-protein and PKC.
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PMID:Cholera toxin and dibutyryl cyclic adenosine 3',5'-monophosphate sensitize gonadotropin-releasing hormone-stimulated inositol phosphate production to inhibition in protein kinase-C (PKC)-depleted cells: evidence for cross-talk between a cholera toxin-sensitive G-protein and PKC. 824

During embryogenesis, neuroblasts proliferate within germinal zones, then migrate to their final positions. Although many neurons migrate along radial glial fibers, evidence suggests that environmental factors, as yet unidentified, also influence neuroblast movement. In vivo, nerve growth factor (NGF) and gamma-aminobutyric acid (GABA) colocalize near target destinations of migratory neuroblasts. In vitro, embryonic spinal neurons migrate towards NGF and GABA (Behar et al.: J Neurosci 14:29-38, 1994), implying that the molecules may act as chemoattractants in vivo. Here, we have used an in vitro assay of migration to show that migratory responses to these attractants develop along a ventrodorsal gradient that parallels terminal mitosis during cord development, and that GABA stimulates chemokinesis (motility without a gradient) via heterogeneous receptors involving separate signalling pathways. Both GABAA (muscimol) and GABAB (baclofen) agonists mimicked the effects of GABA in stimulating chemokinesis. Muscimol-induced motility was only blocked by GABAA antagonists (bicuculline or picrotoxin), whereas migration to baclofen was blocked by antagonists of both GABAA and GABAB (2-hydroxysaclofen) receptors. Migration to baclofen, but not muscimol, was abolished in the presence of 8-bromo cAMP or pertussis toxin, indicating that the former, but not the latter, attractant may stimulate motility via Gi/Go GTP binding proteins, and that PKA may modulate migratory responses to baclofen. Migration to GABA was partially attenuated by each of the GABA receptor antagonists. These results lead us to conclude that the natural ligand stimulates neuroblast motility via heterogeneous receptors coupled to different signalling mechanisms.
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PMID:GABA-induced motility of spinal neuroblasts develops along a ventrodorsal gradient and can be mimicked by agonists of GABAA and GABAB receptors. 853 Dec 31

Purified bovine renal papillary Na+ channels, when reconstituted into planar lipid bilayers, reside in three conductance states: a 40-pS main state, and two subconductive states (12-13 pS and 24-26 pS). The activity of these channels is regulated by phosphorylation and by G-proteins. Protein kinase A (PKA)-induced phosphorylation increased channel activity by increasing the open state time constants from 160 +/- 30 (main conductance), and 15 +/- 5 ms (both lower conductances), respectively, to 365 +/- 30 ms for all of them. PKA phosphorylation also altered the closed time of the channel from 250 +/- 30 ms to 200 +/- 35 ms, thus shifting the channel into a lower-conductance, long open time mode. PKA phosphorylation increased the PNa:PK of the channel from 7:1 to 20:1, and shifted the amiloride inhibition curve to the right (apparent K(i)amil from 0.7 to 20 microM). Pertussis toxin-induced ADP-ribosylation of either phosphorylated of either phosphorylated or nonphosphorylated channels decreased the PNa:PK to 2:1 and 4:1, respectively, and altered K(i)amil to 8 and 2 microM for phosphorylated and nonphosphorylated channels, respectively. GTP-gamma-S treatment of either phosphorylated or nonphosphorylated channels resulted in an increase of PNa:PK to 30:1 and 10:1, respectively, and produced a leftward shift in the amiloride dose-response curve, altering K(i)amil to 0.5 and 0.1 microM, respectively. These results suggest that amiloride-sensitive renal Na+ channel biophysical characteristics are not static, but depend upon the biochemical state of the channel protein and/or its associated G-protein.
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PMID:Biochemical status of renal epithelial Na+ channels determines apparent channel conductance, ion selectivity, and amiloride sensitivity. 858 Mar 22

Experiments were designed to test if immunopurified outwardly rectified chloride channels (ORCCs) and the cystic fibrosis transmembrane conductance regulator (CFTR) incorporated into planar lipid bilayers are regulated by G-proteins. pertussis toxin (PTX) (100 ng/ml) + NAD (1 mM) + ATP (1 mM) treatment of ORCC and CFTR in bilayers resulted in a 2-fold increase in single channel open probability (Po) of ORCC but not of CFTR. Neither PTX, NAD, nor ATP alone affected the biophysical properties of either channel. Further, PTX conferred a linearity to the ORCC current-voltage curve, with a slope conductance of 80 +/- 3 picosiemens (pS) in the +/- 100 mV range of holding potentials. PKA-mediated phosphorylation of these PTX + NAD-treated channels further increased the Po of the linear 80-pS channels from 0.66 +/- 0.05 to >0.9, and revealed the presence of a small (16 +/- 2 pS) linear channel in the membrane. PTX treatment of a CFTR-immunodepleted protein preparation incorporated into bilayer membranes resulted in a similar increase in the Po of the larger conductance channel and restored PKA-sensitivity that was lost after CFTR immunodepletion. The addition of guanosine 5'-3-O-(thio)triphosphate (100 mum) to the cytoplasmic bathing solutions decreased the activity of the ORCC and increased its rectification at both negative and positive voltages. ADP-ribosylation of immunopurified material revealed the presence of a 41-kDa protein. These results demonstrate copurification of a channel-associated G-protein that is involved in the regulation of ORCC function.
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PMID:G-protein regulation of outwardly rectified epithelial chloride channels incorporated into planar bilayer membranes. 861 45


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