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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Membrane currents activated by bradykinin (500 nM) and by extracellular ATP (50 microM) were studied in voltage-clamped, NGF-treated rat pheochromocytoma (PC12) cells. Under quasiphysiological ionic conditions, both substances caused an outward current due to opening of Ca(2+)-activated K+ channels. Bradykinin caused an additional inward current that could be studied after blockade by internal Cs+ of the initial transient outward current. The inward current became larger when the extracellular Ca2+ concentration was increased. Neither inositol-1,4,5-trisphosphate, dioctanoylglycerol, phorbol 12-myristat 13-acetate, forskolin, GTP, GTP-gamma-S, or pretreatment with pertussis toxin affected this current component. Increasing the internal Ca buffer concentration [EGTA or bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetra-acetic acid] from 1 to 10 mM had no effect on the inward current as long as the free [Ca2+]i was kept constant. However, it was modulated by the resting free [Ca2+]i. Elevation of [Ca2+]i from nominally 0 to 60 or to 180 nM increased the bradykinin-induced average peak current density from 0.14 to 1.04 or to 2.29 pA/pF, respectively. This regulation may depend on a calmodulin-dependent pathway, since CGS 9343B, a calmodulin inhibitor, blocked the effect of elevated [Ca2+]i. With ATP as an agonist, outward current was preceded by a large inward current that was partially blocked by extracellular Ca2+ in the millimolar range. Extracellular Ca2+ was also found to reduce the single-channel conductance estimated from outside-out patches treated with ATP.
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PMID:Regulation of bradykinin- and ATP-activated Ca(2+)-permeable channels in rat pheochromocytoma (PC12) cells. 166 May 37

We present evidence that the morphoregulatory activities of neural cell adhesion molecule (NCAM) and N-cadherin involve activation of intracellular second messenger pathways. PC12 cells were cultured on monolayers of control 3T3 cells or 3T3 cells expressing transfected N-cadherin or NCAM. NCAM and N-cadherin directly induced a transcription-independent change in the morphology of PC12 cells from an adrenal to neuronal phenotype and also specifically increased Thy-1, but not L1/NILE or low affinity NGF receptor, immunoreactivity. The morphological response was more rapid and, in the case of N-cadherin, more substantial than that induced by NGF. It could be fully inhibited by pertussis toxin and a combination of L- and N-type Ca2+ channel antagonists, but not by broad-specificity kinase inhibitors. It was blocked, however, by the kinase inhibitor K-252b. These studies suggest that cell adhesion molecules directly alter cell phenotype and provide direct evidence for transmembrane signaling mediating both the morphological and biochemical responses induced by NCAM and N-cadherin.
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PMID:Morphoregulatory activities of NCAM and N-cadherin can be accounted for by G protein-dependent activation of L- and N-type neuronal Ca2+ channels. 168 May 64

We present evidence that the neurite out-growth stimulated by the binding of Thy-1 antibodies to PC12 cells is mediated by calcium influx through both N- and L-type calcium channels. PC12 cells cultured on a noncellular substratum in the presence of NGF, or on a cellular substratum in the absence of NGF, responded to soluble Thy-1 antibody by extending longer neurites. The response required bivalent antibody and could be blocked by removing Thy-1 from the surface of PC12 cells with phosphatidylinositol specific phospholipase C. The response could also be blocked by reducing extracellular calcium to 0.25 mM, or by antagonists of L- and N-type calcium channels. Additionally, the response could be fully inhibited by preloading PC12 cells with BAPTA/AM which buffers changes in intracellular calcium. A heterotrimeric G-protein is also implicated in the pathway as the response could be fully inhibited by pertussis toxin. These data suggest that antibody-induced clustering of Thy-1 stimulates neurite outgrowth by activating a second messenger pathway that has previously been shown to underlie cell adhesion molecule (NCAM, N-cadherin, and L1), but not integrin or NGF-dependent neurite outgrowth.
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PMID:Thy-1 antibody-triggered neurite outgrowth requires an influx of calcium into neurons via N- and L-type calcium channels. 810 Feb 30

The Deleted in Colorectal Cancer (DCC) gene is a candidate tumor suppressor gene that is predicted to encode a transmembrane polypeptide with strong similarity to the neural cell adhesion molecule (N-CAM) family. Previous studies have suggested that several different N-CAMs, when expressed in non-neuronal cell types can stimulate neurite outgrowth from PC12 rat pheochromocytoma cells. Based on the predicted structural similarity of DCC to N-CAMs, we sought to determine whether NIH3T3 cells expressing DCC could stimulate neurite outgrowth in PC12 cells. We found that NIH3T3 cell lines expressing DCC could stimulate PC12 cells to extend neurites. Supernatants from DCC-transfected NIH3T3 cells did not induce neurite outgrowth above background levels, suggesting that cell-cell interaction was required. NIH3T3 cells expressing a truncated form of DCC, lacking the majority of the cytoplasmic domain sequences, also failed to induce neurite outgrowth above the levels seen with control NIH3T3 cells, suggesting that the cytoplasmic domain of DCC was necessary for its neurite-promoting function. In contrast to NGF-mediated neurite outgrowth, the DCC-mediated response was inhibited by treatment with pertussis toxin or the combination of N- and L-type calcium channel blockers, and was unaffected by the transcriptional inhibitor cordycepin. The data suggest that the DCC protein can function in a fashion analogous to other N-CAMs to alter PC12 cell phenotype through intracellular pathways distinct from those involved in NGF signaling.
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PMID:NIH3T3 cells expressing the deleted in colorectal cancer tumor suppressor gene product stimulate neurite outgrowth in rat PC12 pheochromocytoma cells. 813 5

The effect of proadrenomedullin NH2-terminal 20 peptide (PAMP) on the voltage-gated Ca2+ channel current was investigated using the perforated whole-cell clamp technique on NGF-treated PC12 cells. PAMP inhibited the Ba2+ current through N-type Ca2+ channels in a concentration dependent manner. Injection of GDPbetaS into the cell abolished the inhibition while injection of GTPgammaS into the cell made the inhibition irreversible, indicating that the PAMP-induced inhibition of the voltage-gated Ca2+ channel was mediated by a G protein. The inhibition was abolished by pretreating the cells with pertussis toxin, indicating that a pertussis toxin-sensitive G protein was involved in the signal transduction mechanism of PAMP. The present study revealed that the inhibition of catecholamine secretion from sympathetic nerve endings by PAMP could be explained by the inhibition of N-type Ca2+ channels, which was mediated by pertussis toxin-sensitive G protein.
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PMID:Proadrenomedullin NH2-terminal 20 peptide inhibits the voltage-gated Ca2+ channel current through a pertussis toxin-sensitive G protein in rat pheochromocytoma-derived PC 12 cells. 869 Jul 85

The roles of G(o), a heterotrimeric GTP binding (G) protein with a 40-kDa alpha subunit and which is localized predominantly in neuronal cells, in exocytosis have been discussed recently. PC12 pheochromocytoma cell line is a convenient model in which to study the Ca(2+)-dependent mechanisms of the neurosecretory process. The stimulation of ATP receptors or addition of KCl stimulated an elevation of cytosolic free Ca2+ concentration ([Ca2+]i) and [3H]noradrenaline (NA) release in PC12 cells. In this study, we investigated the roles of G(o) in ATP- and KCl-stimulated reactions. Nerve growth factor treatment for 2 days and transfection of PC12 cells with cDNA of subunit of (G(o alpha) had no effect on ATP-stimulated [3H]NA release, although both treatments increased levels of the G(o alpha) and its trimeric form by about twofold over those in unstimulated cells. The [Ca2+]i rise induced by ATP in NGF-treated cells was similar to that in control cells, although the maximal response was slightly smaller. Cholera toxin treatment for 2 days inhibited ATP- and KCl-stimulated NA release, although this treatment caused an approximately twofold increase in the level of G(o). Pertussis toxin treatment, which ADP ribosylated over 90% of endogenous G proteins such as G(o), had no effect on ATP-stimulated reactions. These findings show that G(o) does not directly regulate ATP-stimulated Ca2+ channels or the NA release process in PC12 cells. Cholera toxin-sensitive protein(s) may regulate exocytosis.
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PMID:G(o) protein does not regulate ATP-stimulated [Ca2+]i elevation or noradrenaline release in PC12 cells. 880 2

Sphingosine-1-phosphate (SPP), a bioactive sphingolipid metabolite, suppresses apoptosis of many types of cells, including rat pheochromocytoma PC12 cells. Elucidating the molecular mechanism of action of SPP is complicated by many factors, including uptake and metabolism, as well as activation of specific G-protein-coupled SPP receptors, known as the endothelial differentiation gene-1 (EDG-1) family. In this study, we overexpressed type 1 sphingosine kinase (SPHK1), the enzyme that converts sphingosine to SPP, in order to examine more directly the role of intracellularly generated SPP in neuronal survival. Enforced expression of SPHK1 in PC12 cells resulted in significant increases in kinase activity, with corresponding increases in intracellular SPP levels and concomitant decreases in both sphingosine and ceramide, and marked suppression of apoptosis induced by trophic factor withdrawal or by C(2)-ceramide. NGF, which protects PC12 cells from serum withdrawal-induced apoptosis, also stimulated SPHK1 activity. Surprisingly, overexpression of SPHK1 had no effect on activation of two known NGF-stimulated survival pathways, extracellular signal regulated kinase ERK 1/2 and Akt. However, trophic withdrawal-induced activation of the stress activated protein kinase, c-Jun amino terminal kinase (SAPK/JNK), and activation of the executionary caspases 2, 3 and 7, were markedly suppressed. Moreover, this abrogation of caspase activation, which was prevented by the SPHK inhibitor N,N-dimethylsphingosine, was not affected by pertussis toxin treatment, indicating that the cytoprotective effect was likely not mediated by binding of SPP to cell surface G(i)-coupled SPP receptors. In agreement, there was no detectable release of SPP into the culture medium, even after substantially increasing cellular SPP levels by NGF or sphingosine treatment. In contrast to PC12 cells, C6 astroglioma cells secreted SPP, suggesting that SPP might be one of a multitude of known neurotrophic factors produced and secreted by glial cells. Collectively, our results indicate that SPHK/SPP may play an important role in neuronal survival by regulating activation of SAPKs and caspases.
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PMID:Sphingosine kinase expression regulates apoptosis and caspase activation in PC12 cells. 1123 41

P2Y receptors inhibiting adenylyl cyclase have been found in blood platelets, glioma cells, and endothelial cells. In platelets and glioma cells, these receptors were identified as P2Y(12). Here, we have used PC12 cells to search for adenylyl cyclase inhibiting P2Y receptors in a neuronal cellular environment. ADP and ATP (0.1 - 100 microM) left basal cyclic AMP accumulation unaltered, but reduced cyclic AMP synthesis stimulated by activation of endogenous A(2A) or recombinant beta(2) receptors. Forskolin-dependent cyclic AMP production was reduced by <or=1 microM and enhanced by 10 - 100 microM ADP; this latter effect was turned into an inhibition when A(2A) receptors were blocked. The nucleotide inhibition of cyclic AMP synthesis was not altered when P2X receptors were blocked, but abolished by pertussis toxin. The rank order of agonist potencies for the reduction of cyclic AMP was (IC(50) values): 2-methylthio-ADP (0.12 nM)=2-methylthio-ATP (0.13 nM)>ADPbetaS (71 nM)>ATP (164 nM)=ADP (244 nM). The inhibition by ADP was not antagonized by suramin, pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid, or adenosine-3'-phosphate-5'-phosphate, but attenuated by reactive blue 2, ATP(alpha)S, and 2-methylthio-AMP. RT - PCR demonstrated the expression of P2Y(2), P2Y(4), P2Y(6), and P2Y(12), but not P2Y(1), receptors in PC12 cells. In Northern blots, only P2Y(2) and P2Y(12) were detectable. Differentiation with NGF did not alter these hybridization signals and left the nucleotide inhibition of adenylyl cyclase unchanged. We conclude that P2Y(12) receptors are expressed in neuronal cells and inhibit adenylyl cyclase activity.
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PMID:Inhibition of adenylyl cyclase by neuronal P2Y receptors. 1183 15

Purkinje cell protein-2 (Pcp2 or L7) is highly expressed in cerebellar Purkinje cells and retinal bipolar neurons and interacts with the Galpha(i/o) family of G-proteins. Although the expression pattern of Pcp2 in the developing central nervous system suggests a role in differentiation, its function remains unknown. We established Tet-off inducible expression of Pcp2 in PC12 cells (rat pheochromocytoma cells) to determine whether Pcp2 regulates neuronal differentiation. Utilizing a polyclonal antibody, Pcp2 was localized in the cell body and throughout neurites of differentiated PC12 cells, similar to its localization in cerebellar Purkinje cells. Pcp2 expression in PC12 cells stimulated process formation (5-fold) and NGF (nerve growth factor)-stimulated neurite length (2-fold). Under basal conditions, Pcp2-PC12 cells demonstrated a 5-fold increase in Ras activation relative to non-induced PC12 cells and there was no change in extracellular-signal-regulated kinase 1/2 activity with Pcp2 expression. However, Pcp2 induction led to a >3-fold increase in basal p38 MAPK (mitogen-activated protein kinase) activity and the addition of NGF significantly stimulated both Ras and p38 MAPK in Pcp2-PC12 cells relative to the controls. Pretreatment of Pcp2-PC12 cells with the p38-specific inhibitor SB203580 blocked both the increased neurite formation and NGF-stimulated neurite growth. Pertussis toxin treatment had no effect on neurite growth in control cells, but completely blocked Pcp2-mediated increased neurite growth. Transient transfection of the beta-adrenergic receptor kinase C-terminus to prevent signalling through Gbetagamma in Pcp2-PC12 cells also inhibited the Pcp2-induced phenotype and reduced the Pcp2-stimulated Ras activation. Taken together, these findings demonstrate that Pcp2 induces differentiation in PC12 cells, in part through Gbetagamma-mediated Ras and p38 MAPK activation and suggest the potential for similar signalling mechanisms in Purkinje cells.
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PMID:Purkinje cell protein-2 (Pcp2) stimulates differentiation in PC12 cells by Gbetagamma-mediated activation of Ras and p38 MAPK. 1594 14

C3a and C5a anaphylatoxins are proinflammatory polypeptides released during complement activation. They exert their biological activities through interaction with two G protein-coupled receptors named C3aR and C5aR, respectively. In the brain, these receptors are expressed on glial cells, and some recent data have suggested that anaphylatoxins could mediate neuroprotection. In this study, we used RT-PCR and ribonuclease protection assays (RPA) to investigate the role of anaphylatoxins on neurotrophin expression by the human glioblastoma cell line T98G and by rat astrocytes. Our data show that for both cell types, anaphylatoxins upregulate expression of NGF mRNA. This response depended on a G protein-coupled pathway since pre-treatment of cells with pertussis toxin (PTX) completely blocked NGF mRNA increases. This effect was anaphylatoxin-specific since pre-incubation with anti-C3a or anti-C5aR antibodies abolished the effects of C3a and C5a, respectively. The regulation of NGF mRNA by anaphylatoxins was not accompanied by translation into protein expression, but there was a significant synergic effect of anaphylatoxins/IL-1b costimulation. Our demonstration of involvement of anaphylatoxins in the NGF release process by astrocytes suggests that C3a and C5a could modulate neuronal survival in the CNS.
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PMID:Interleukin-1beta and anaphylatoxins exert a synergistic effect on NGF expression by astrocytes. 1659 97


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