Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We asked if the mechanisms of exocytosis and its regulation in epithelial cells share features with those in excitable cells. Cultured dog pancreatic duct epithelial cells were loaded with an oxidizable neurotransmitter, dopamine or serotonin, and the subsequent release of these exogenous molecules during exocytosis was detected by carbon-fiber amperometry. Loaded cells displayed spontaneous exocytosis that may represent constitutive membrane transport. The quantal amperometric events induced by fusion of single vesicles had a rapid onset and decay, resembling those in adrenal chromaffin cells and serotonin-secreting leech neurons. Quantal events were frequently preceded by a "foot," assumed to be leak of transmitters through a transient fusion pore, suggesting that those cell types share a common fusion mechanism. As in neurons and endocrine cells, exocytosis in the epithelial cells could be evoked by elevating cytoplasmic Ca(2+) using ionomycin. Unlike in neurons, hyperosmotic solutions decreased exocytosis in the epithelial cells, and giant amperometric events composed of many concurrent quantal events were observed occasionally. Agents known to increase intracellular cAMP in the cells, such as forskolin, epinephrine, vasoactive intestinal peptide, or 8-Br-cAMP, increased the rate of exocytosis. The forskolin effect was inhibited by the Rp-isomer of cAMPS, a specific antagonist of protein kinase A, whereas the Sp-isomer, a specific agonist of PKA, evoked exocytosis. Thus, PKA is a downstream effector of cAMP. Finally, activation of protein kinase C by phorbol-12-myristate-13-acetate also increased exocytosis. The PMA effect was not mimicked by the inactive analogue, 4alpha-phorbol-12,13-didecanoate, and it was blocked by the PKC antagonist, bisindolylmaleimide I. Elevation of intracellular Ca(2+) was not needed for the actions of forskolin or PMA. In summary, exocytosis in epithelial cells can be stimulated directly by Ca(2+), PKA, or PKC, and is mediated by physical mechanisms similar to those in neurons and endocrine cells.
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PMID:Regulation of exocytosis by protein kinases and Ca(2+) in pancreatic duct epithelial cells. 1100 1

The direct effects of pituitary adenylate cyclase-activating polypeptides (PACAP) on sympathetic neurons were investigated using rat superior cervical ganglion neurons. Electrophysiological and pharmacological analyses were used to evaluate PACAP modulation of sympathetic neuron membrane potentials and to investigate potential ionic and intracellular signaling mechanisms mediating the responses. More than 90% of the sympathetic neurons were depolarized by the PACAP peptides even when stimulated release was blocked, indicating that the PACAP peptides elicited primary responses in the postganglionic neurons. The response profile was consistent for activation of PACAP-selective PAC(1) receptors: nanomolar concentrations of PACAP27 and PACAP38 were required to stimulate depolarization, whereas vasoactive intestinal peptide failed to evoke any response. Furthermore, depolarizations elicited by PACAP27 were reduced by the PAC(1) receptor antagonist PACAP(6-38). Both sodium influx and inhibition of a potassium current contributed to the peptide-induced depolarizations. Activation of neither pertussis toxin- nor cholera toxin-sensitive G-proteins was required for generation of the depolarizations. cAMP and diacylglycerol production and activation of protein kinase A or protein kinase C also were not requisite for the responses. By contrast, phospholipase C (PLC)-dependent inositol 1,4,5-triphosphate (IP(3)) synthesis was crucial to the PACAP-mediated depolarizations. Although calcium release from IP(3)-sensitive stores was not required for the PACAP-induced responses, inhibition of IP(3) receptors reduced the depolarizations. Thus, among the many signal transduction pathways coupled to the PAC(1) receptor, the PACAP-induced depolarization of sympathetic neurons appears to require activation of PLC and subsequent generation of IP(3).
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PMID:Mechanisms mediating pituitary adenylate cyclase-activating polypeptide depolarization of rat sympathetic neurons. 1100 93

The vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase activating polypeptide (PACAP), two immunomodulatory neuropeptides that affect both innate and acquired immunity, downregulate TNFalpha expression in LPS-stimulated peritoneal macrophages and Raw 264.7 cells. We showed previously that VIP/PACAP change the composition of the CRE-binding complex in the TNFalpha promoter from highc-Jun/(low)CREB, characteristic for LPS-stimulated macrophages, to lowc-Jun/(high)CREB, characteristic for the unstimulated cells. In the present study we examined the effects of VIP/PACAP on the MEKK1/MEK4/JNK transduction pathway, and on the subsequent changes in Jun family members. Our studies indicate that VIP/PACAP inhibit MEKK1 activity, and the subsequent phosphorylation of MEK4, JNK, and c-Jun. Treatment with VIP or PACAP results in a decrease in AP-1 binding, and a marked change in the composition of the AP-1 complexes from c-Jun/c-Fos to JunB/c-Fos. Western blots confirm that VIP stimulates JunB production in LPS-stimulated macrophages. Both the inhibition of the MEKK1/MEK4/JNK pathway, leading to the reduction in phosphorylated c-Jun, and the stimulation of JunB, are mediated through the specific VPAC1 receptor and the cAMP/PKA pathway. The VIP/PACAP interference with the stress-induced SAPK/JNK pathway in stimulated macrophages may represent a significant element in the regulation of the inflammatory response by the endogenous neuropeptides.
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PMID:Vasoactive intestinal peptide and pituitary adenylate cyclase activating polypeptide inhibit the MEKK1/MEK4/JNK signaling pathway in LPS-stimulated macrophages. 1102 38

The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) suppress monocyte/macrophage production of proinflammatory agents. The transcription factor NF-kappa B regulates the transcription of most agents. VIP/PACAP inhibit NF-kappa B transactivation in the lipopolysaccharide-stimulated human monocytic cell line THP-1 at multiple levels. First, VIP/PACAP inhibit p65 nuclear translocation and NF-kappa B DNA binding by stabilizing the inhibitor I kappa B alpha. Second, VIP/PACAP induce phosphorylation of the CRE-binding protein (CREB) and its binding to the CREB-binding protein (CBP). This results in a decrease in p65.CBP complexes, which further reduces NF-kappa B transactivation. Third, VIP and PACAP reduce the phosphorylation of the TATA box-binding protein (TBP), resulting in a reduction in TBP binding to both p65 and the TATA box. All these effects are mediated through the specific receptor VPAC1. The cAMP/cAMP-dependent protein kinase pathway mediates the effects on CBP and TBP, whereas a cAMP-independent pathway is the major transducer for the effects on p65 nuclear translocation. Since NF-kappaB represents a focal point for various stimuli and induces the expression of many proinflammatory genes, its targeting by VIP and PACAP positions them as important anti-inflammatory agents. The VIP/PACAP inhibition of NF-kappa B at various levels and through different transduction pathways could offer a significant advantage over other anti-inflammatory agents.
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PMID:Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit nuclear factor-kappa B-dependent gene activation at multiple levels in the human monocytic cell line THP-1. 1102 67

Cis-unsaturated free fatty acids (FFA) like oleic acid are strong blockers of both basal and stimulated GH secretion in vivo by acting directly on the somatotroph cell. Several lines of evidence suggest that this inhibitory action is the result of a perturbation of the function of several plasma membrane integral proteins. It has been reported recently that cis-FFA are able to block several steps in the inositolphosphates/phospholipase C/Ca2+ (InsPs/PLC/Ca2+) signal transduction pathway triggered by the activation of the TRH receptor. In this paper we present evidence showing that the inhibition of growth hormone (GH) and prolactin (PRL) secretion by cis-FFA in vitro is also exerted at several different levels on the cAMP-protein kinase A (cAMP/PKA) pathway triggered by the stimulation of the vasoactive intestinal peptide (VIP) receptor in pituitary clonal cells. By means of a sequential analysis of signal transduction events, we observed that cis-unsaturated FFA; (1) reduce the activity of adenylate cyclase; (2) perturb the activity of protein kinase A; (3) suppress the VIP-triggered Ca2+ influx, and (4) do not perturb VIP binding or the homologous desensitization of the VIP receptor.
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PMID:Cis-unsaturated free fatty acids block VIP-mediated GH and PRL secretion by perturbing the cAMP/protein kinase A pathway. 1108 Nov 80

The effects of prostaglandin E2 (PGE2) and vasoactive intestinal peptide (VIP) on vascular endothelial cell growth factor (VEGF) mRNAs were investigated using lung cancer cells. By RT-PCR, VEGF(121), VEGF(165), and VEGF(189), but not VEGF(206) isoforms were detected in all lung cancer cell lines and biopsy specimens examined. By Northern blot, VEGF mRNA was detected in all small cell lung cancer (SCLC) and non-SCLC (NSCLC) cell lines examined. PGE2, VIP and forskolin caused increased VEGF expression in a time- and concentration-dependent manner using NSCLC cell line NCI-H157. Approximately 1 microM PGE2, 0.1 microM VIP and 50 microM forskolin caused cAMP elevation, 64-, 33- and 128-fold, respectively, using NCI-H157 cells after 5 min. The increase in cAMP caused by PGE(2) and VIP was reversed by somatostatin (SST). Also 1 microM PGE2, 0.1 microM VIP and 50 microM forskolin increased the VEGF mRNA 2.0-, 1.5- and 2.3-fold, respectively, after 4 h. The increase in VEGF mRNA caused by PGE2, VIP and forskolin was inhibited by H-89, a protein kinase A inhibitor. A VIP receptor antagonist, VIPhybrid, inhibited the increase in cAMP and VEGF mRNA caused by VIP. By ELISA, VEGF was detected in the conditioned media exposed to the lung cancer cell lines. These results suggest that VEGF synthesis in and secretion from lung cancer cells can be regulated by agents, which cause adenylyl cyclase activation.
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PMID:Prostaglandin E2 and vasoactive intestinal peptide increase vascular endothelial cell growth factor mRNAs in lung cancer cells. 1116 99

Recent progress in research on pituitary adenylate-activating polypeptide (PACAP) with a special emphasis on the brain is reviewed. PACAP is a pleiotropic neuropeptide that belongs to the secretin/glucagon/vasoactive intestinal peptide family. PACAP functions as a hypothalamic hormone, neurotransmitter, neuromodulator, and neurotrophic factor. Studies on the gene encoding the PACAP precursor and the specific PACAP receptor (PAC1-R) and its subtypes have provided information on the control of gene expression for PACAP, and the relationship between the receptor subtypes and the signal transduction pathways. The PAC1-R is a G protein-coupled receptor with seven transmembrane domains and belongs to the VIP receptor family. At least eight subtypes of PAC1-R result from alternate splicing. Each subtype is coupled to specific signaling pathways, and its expression is tissue or cell specific. PACAP stimulates the release of arginine vasopressin and increases cytosolic Ca2+ ([Ca2+]i). PACAP serves as a neurotransmitter and/or neuromodulator and the activation of the PAC1-R stimulates a cAMP-protein kinase A signal transduction pathway which in turn evokes the [Ca2+]i signaling system. More importantly, PACAP is a neurotrophic factor that may play an important role during the development of the brain. The PAC1-R is actively expressed in different neuroepithelia from early developmental stages and expressed in various brain regions during prenatal and postnatal development. In the adult brain, PACAP appears to function as a neuroprotective factor that attenuates the neuronal damage resulting from various insults.
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PMID:Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors in the brain. 1119 92

1. The spasmolytic and anti-spasmogenic activity of beta-adrenoceptor agonists on airways smooth muscle is thought to involve activation of the cyclic AMP/cyclic AMP-dependent protein kinase (PKA) cascade. Here we have tested the hypothesis that PKA mediates the anti-spasmogenic activity of isoprenaline and other cyclic AMP-elevating agents in guinea-pig isolated trachea by utilizing a number of cell permeant cyclic AMP analogues that act as competitive 'antagonists' of PKA. 2. Anion-exchange chromatography of guinea-pig tracheae resolved two peaks of PKA activity that corresponded to the type I ( approximately 5%) and type II ( approximately 93%) isoenzymes. 3. Pre-treatment of tracheae with zardaverine (30 microM), vasoactive intestinal peptide (VIP) (1 microM) and the non-selective activator of PKA, Sp-8-CPT-cAMPS (10 microM), produced a non-parallel rightwards shift in the concentration-response curves that described acetylcholine (ACh)-induced tension generation. The type II-selective PKA inhibitor, Rp-8-CPT-cAMPS (300 microM), abolished this effect. 4. Pre-treatment of tracheae with Sp-8-Br-PET-cGMPS (30 microM) produced a non-parallel rightwards shift of the concentration-response curves that described ACh-induced tension generation. The selective cyclic GMP-dependent protein kinase (PKG) inhibitor, Rp-8-pCPT-cGMPS (300 microM), abolished this effect. 5. Pre-treatment of tracheae with isoprenaline (1 microM) produced a 10 fold shift to the right of the ACh concentration-response curve by a mechanism that was unaffected by Rp-8-Br-cAMPS (300 microM, selective inhibitor of type I PKA), Rp-8-CPT-cAMPS (300 microM) and Rp-8-pCPT-cGMPS (300 microM). 6. We conclude that the anti-spasmogenic activity of Sp-8-CPT-cAMPS, zardaverine and VIP in guinea-pig trachea is attributable to activation of the cyclic AMP/PKA cascade whereas isoprenaline suppresses ACh-induced contractions by a mechanism(s) that is independent of PKA and PKG.
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PMID:Evidence that the anti-spasmogenic effect of the beta-adrenoceptor agonist, isoprenaline, on guinea-pig trachealis is not mediated by cyclic AMP-dependent protein kinase. 1149 3

The vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP), two immunomodulatory neuropeptides, act as anti-inflammatory factors for activated microglia, by inhibiting the production of proinflammatory factors. In the present study the effects of VIP/PACAP on the MEKK1/MEK4/JNK transduction pathway and on the subsequent changes in Jun family members, a transduction pathway clearly involved in the activation of microglia cells were examined. VIP/PACAP inhibit MEKK1 activity and the subsequent phosphorylations of MEK4, JNK, and c-Jun, which result in a decrease in the AP-1 binding and a marked change in the composition of AP-1 complexes from c-Jun/c-Fos to JunB/c-Fos. Furthermore, VIP stimulates JunB production in LPS-stimulated microglia. Both inhibition of the MEKK1/MEK4/JNK pathway, leading to a reduction in phosphorylated c-Jun, and the stimulation of JunB are mediated through the specific VPAC1 receptor and cAMP/PKA pathway. The VIP/PACAP interference with the stress-induced SAPK/JNK pathway in activated microglia may represent a significant element in the regulation of inflammatory response in the CNS by endogenous neuropeptides.
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PMID:Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit the MEKK1/MEK4/JNK signaling pathway in endotoxin-activated microglia. 1205 37

MUC5AC mucin is not expressed in normal pancreas but is expressed in tumors. Little is known about the mechanisms that lead to this atypical expression. In this study, we demonstrate that stimulation of adenylyl cyclase and the protein kinase A (PKA) pathway by forskolin and vasoactive intestinal peptide (VIP) increased MUC5AC antigen expression and release from pancreatic cancer cells. Stimulation of the PKA pathway also increased MUC5AC mRNA. When SW1990 pancreatic cancer cells were grown on porous membranes they released MUC5AC mucins apically in response to VIP (10(-7) M) applied to their basolateral surfaces. SW1990 cells, as have been reported for other pancreatic cancer cells, have high affinity (<10(-7) M) VIP receptors and low affinity (>10(-6) M) secretin receptors. We also showed that four antibodies (CLH2, 21M1, 45M1, and Nd2) react with MUC5AC antigen in different cellular compartments of both tissues and cultured cells. In conclusion, the PKA pathway may contribute to the up-regulation of MUC5AC expression seen in pancreatic tumors.
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PMID:Secretion of MUC5AC mucin from pancreatic cancer cells in response to forskolin and VIP. 1205 23


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