Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

[Met5]-Enkephalin (ME) secretion and the expression of proenkephalin A (proENK) mRNA were studied following long-term exposure of bovine adrenal medullary chromaffin (BAMC) cells to pertussis toxin. Treatment with pertussis toxin for 24 h increased the secretion of ME in a concentration- and time-dependent manner. The magnitude of ME secretion continued to increase with time in the presence of pertussis toxin. The intracellular concentration of ME in the pertussis toxin-treated group was not significantly different from controls, suggesting that elevated levels of ME secretion result from increased biosynthesis of ME rather than from release of stored ME. Prolonged (24 h) stimulation of BAMC cells with pertussis toxin also increased proENK gene expression. Pretreatment with nimodipine (a calcium channel blocker) and calmidazolium (a calmodulin antagonist) inhibited both the secretion of ME and the increase in proENK mRNA levels induced by pertussis toxin, while the intracellular calcium antagonist dantrolene and the protein kinase C inhibitors sphingosine and H7 [1-(5-isoquinolinylsulfonyl)-2-methylpiperazine] were ineffective in blocking pertussis toxin-induced responses. Forskolin (an adenyl cyclase activator) and isobutyl methyl xanthine (a phosphodiesterase inhibitor) increased both ME secretion and proENK mRNA levels; pertussis toxin synergistically increased the secretion of ME with these cyclic AMP-elevating agents but had only an additive effect with these agents on the level of proENK mRNA. Our results suggest that a pertussis toxin-sensitive G protein may tonically regulate the secretion of ME as well as the level of proENK mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pertussis toxin stimulates the secretion of [Met5]-enkephalin and the expression of proenkephalin A mRNA in bovine adrenal medullary chromaffin cells. 128 24

The synthesis of the neuropeptide precursor proenkephalin was measured in bovine adrenal chromaffin cells following radiolabeling with [35S]methionine. Treatment of chromaffin cells with pertussis toxin (100 ng/ml) approximately doubled proenkephalin synthesis without altering total protein synthesis. Pertussis toxin pretreatment also increased proenkephalin synthesis in chromaffin cells exposed to vasoactive intestinal peptide (VIP) and 3-isobutyl-1-methylxanthine (IBMX). Combinations of IBMX plus nicotine, VIP, or histamine also synergistically enhanced proenkephalin synthesis, with no further elevation when the cells were also pretreated with pertussis toxin. The action of forskolin, a direct activator of adenylate cyclase, on proenkephalin synthesis was similarly potentiated by pertussis toxin or IBMX, presumably reflecting the abilities of both the toxin and this phosphodiesterase inhibitor to enhance the cyclic AMP response to forskolin. In contrast, increased synthesis of proenkephalin in response to phorbol esters was not affected by pertussis toxin treatment. These results suggest that pertussis toxin potentiates proenkephalin synthesis primarily through inactivation of guanine nucleotide-binding proteins that inhibit adenylate cyclase, although other signaling pathways may also be involved.
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PMID:Pertussis toxin enhances proenkephalin synthesis in bovine chromaffin cells. 769 72

beta-Endorphin (beta-EP) and delta opioid receptor (DOR) agonists affect immune functions such as lymphocyte chemotaxis, proliferation, and cytokine production. Recent studies indicate that both neuronal DOR and novel G-protein-coupled receptors with high affinity for beta-EP and DOR agonists are expressed by mononuclear cells. In addition, proenkephalin A mRNA and enkephalin-related peptides are expressed by lymphocytes. These investigations were conducted to identify signal transduction pathways that mediate the effects of beta-EP and DOR agonists on T cells. Calcium mobilization was studied because it is central to T-cell activation initiated by antigen presentation to the T-cell receptor (TCR). Using the calcium-sensitive dye Fluo-3 and flow cytofluorometry to determine the concentration of free intracellular calcium, physiological concentrations of beta-EP were shown to enhance concanvalin. A (con A)-stimulated calcium mobilization by murine splenic T cells (p < 0.01). The DOR antagonist, naltrindole, inhibited this, whereas CTAP, a selective mu OR antagonist, was ineffective. In addition, N-Ac-beta-EP and the mu OR agonist DAMGO, failed to mimic the effects of beta-EP. Although it was less potent than beta-EP, DADLE, a DOR agonist, also enhanced Con-A-induced calcium mobilization (p < 0.01). A DOR-transfected human T-cell line (DOR-Jul.1) was developed to study signal transduction. Both DADLE and the selective DOR agonist, deltorphin, rapidly increased intracellular free calcium concentrations; ED50s were 10(-9) M. Pertussis toxin prevented the response, and EGTA significantly reduced it. In addition, DADLE inhibited forskolin-stimulated cAMP production (ED50: 10(-11) M). These findings with normal splenic T cells and DOR-transfected T-cell line indicate that beta-EP and DOR agonists affect calcium mobilization. This is likely to modulate downstream pathways that regulate T-cell activation and function.
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PMID:Signaling through delta opioid receptors on murine splenic T cells and stably transfected Jurkat cells. 962 68

In rat astrocytes, incubation with cholera toxin (CTX; 0.1 microg/ml) for 8 h increased proenkephalin (proENK) mRNA level (10-fold), which was further increased by dexamethasone (DEX; 1 microM) (2.2-fold as much as CTX alone). Although pertussis toxin (PTX; 0.1 microg/ml) did not affect the basal proENK mRNA level, DEX significantly increased proENK mRNA level in PTX-treated cells (6-fold). The inhibition of protein synthesis by cycloheximide (CHX; 15 microM) also increased proENK mRNA level in PTX-treated cells (5.2-fold), but not in CTX-stimulated cells. The treatment with CTX, but not PTX, increased c-Fos and Fra-2 protein levels as well as AP-1, CRE, or ENKCRE-2 DNA binding activity, but neither toxin affected Fra-1, c-Jun, JunB, and JunD protein levels. CHX significantly attenuated CTX-induced increase of c-Fos or Fra-2 protein level and AP-1, CRE, or ENKCRE-2 DNA binding activity, although CHX alone did not affect the basal AP-1, CRE, and ENKCRE-2 DNA binding activities. Phosphorylated CREB level was increased by both CTX and PTX, although the magnitude of phosphorylation of CREB by PTX was much less than that by CTX. In addition, CHX further or persistently increased PTX- or CTX-induced phosphorylated CREB levels in parallel with increases in proENK mRNA. However, DEX did not alter the basal or stimulated phosphorylated-CREB level. These results suggest that the elevation of phosphorylation of CREB rather than AP-1 level may be involved in CTX-induced and CHX-dependent-PTX-induced increase of proENK mRNA level. In addition, AP-1 expression or CREB phosphorylation appears not to be involved the potentiative action of DEX on proENK mRNA expression in CTX- and PTX-treated astrocytes.
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PMID:The comparative analysis of proenkephalin mRNA expression induced by cholera toxin and pertussis toxin in primary cultured rat cortical astrocytes. 1129 34

Herpesvirus-mediated transfer of the human preproenkephalin gene to primary afferent nociceptors prevents phasic thermal allodynia/hyperalgesia in mice. It is not known, however, whether similar viral treatments would reverse ongoing or chronic pain and allodynia/hyperalgesia. To this end, mice were given intrathecal injections of pertussis toxin (PTX), which produces a weeks-long thermal hyperalgesia apparently by uncoupling certain G proteins from inhibitory neurotransmitter receptors. This treatment produced profound thermal hyperalgesia in both Adelta and C-fiber thermonociceptive tests lasting at least 6 weeks. However, treatment of skin surfaces with an enkephalin-encoding herpesvirus, but not control virus or vehicle, completely reversed this hyperalgesia. This profound anti-hyperalgesia was observed for both Adelta- and C-fiber-mediated responses. Interestingly, however, while the anti-hyperalgesic effect of the enkephalin-encoding virus on C-fiber-mediated responses was reversed by intrathecal application of micro or delta opioid antagonists, only delta antagonists reversed the effect of this virus on Adelta hyperalgesia. Thus, virus-mediated delivery of the proenkephalin cDNA reverses thermal hyperalgesia produced by PTX-induced ribosylation of inhibitory G proteins by an opioid-mediated mechanism. These results suggest that herpesvirus vectors encoding analgesic peptides may be useful in attenuating centrally mediated, ongoing neuropathic pain and/or hyperalgesia.
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PMID:Reversal of ongoing thermal hyperalgesia in mice by a recombinant herpesvirus that encodes human preproenkephalin. 1474 74

Human sensory neuron-specific G-protein-coupled receptors (SNSRs) are expressed solely in small diameter primary sensory neurons. This restricted expression pattern is of considerable therapeutic interest because small nociceptors transmit chronic pain messages. The neuronal function of human SNSRs is difficult to assess because rodent orthologs have yet to be clearly defined, and individual isoforms are found only in a small subset of primary sensory neurons. To circumvent this problem, we expressed human SNSR4 (hSNSR4; also known as Hs.mrgX1) in rat superior cervical ganglion (SCG), dorsal root ganglion (DRG), and hippocampal neurons using nuclear injection or recombinant adenoviruses and examined modulation of ion channels and neurotransmission using whole-cell patch-clamp techniques. BAM8-22 (a 15 amino acid C-terminal fragment of bovine adrenal medulla peptide 22), a peptide agonist derived from proenkephalin, inhibited high (but not low) voltage-activated Ca2+ current in both DRG and SCG neurons expressing hSNSR4, whereas no response was detected in control neurons. The Ca2+ current inhibition was concentration dependent and partially sensitive to Pertussis toxin (PTX) treatment. Additionally, the peptide was highly effective in modulating current arising from M-type K+ channels in SCG neurons expressing hSNSR4. In hippocampal neurons expressing hSNSR4, BAM8-22 induced presynaptic inhibition of transmission that was abolished after PTX treatment. Our data indicate that hSNSR4, when heterologously expressed in rat neurons, can be activated by an opioid-related peptide, couples to G(q/11)-proteins as well as PTX-sensitive G(i/o)-proteins, and modulates neuronal Ca2+ channels, K+ channels, and synaptic transmission.
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PMID:Modulation of ion channels and synaptic transmission by a human sensory neuron-specific G-protein-coupled receptor, SNSR4/mrgX1, heterologously expressed in cultured rat neurons. 1516 97