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

Airway smooth muscle (ASM) cell proliferation contributes to increased airway resistance in bronchial asthma. We have examined the modulation of ASM proliferation by vasoactive intestinal peptide (VIP), a cotransmitter of airway relaxation. Human ASM cells were grown in culture as a monolayer. VIP (1.0 nM-1.0 microM) inhibited proliferation in a dose-dependent manner by up to 82% on day 2, but the related peptide glucagon had no effect. Histamine (100 nM-100 microM) increased cell counts by 66%, but in the presence of VIP, cell counts and [3H]thymidine incorporation were reduced by up to 55%. Adenosine 3',5'-cyclic monophosphate (cAMP)-promoting agents, including 3-isobutyl-1-methylxanthine, forskolin, and 8-bromo-adenosine 3',5'-cyclic monophosphate, alone and especially combined with VIP, reduced cell counts and [3H]thymidine incorporation, in correlation with cAMP levels. KT-5720 (1.0 nM-1.0 microM), a selective inhibitor of cAMP-dependent protein kinase A (PKA), abolished the inhibitory effect of VIP. The results show that VIP selectively and potently inhibits human ASM cell growth and multiplication, and nullifies the mitogenic effect of histamine, by a PKA-mediated mechanism. A deficiency of VIP may lead to ASM hyperplasia due to unopposed stimulation by endogenous mitogens.
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PMID:VIP inhibits basal and histamine-stimulated proliferation of human airway smooth muscle cells. 754 47

We examined the effects of FK506 on amylase secretion and intracellular pathway in stimulus secretion coupling in isolated pancreatic acini. Amylase release from isolated acini in response to cholecystokinin octapeptide (CCK-8) was suppressed by exposing acini to FK506. The suppressing effect of FK506 on amylase release from acini was dependent on the concentration of FK506 and the time of exposure to FK506. Amylase releases in response to 8-bromo-cAMP and vasoactive intestinal peptide and phorbol ester (12-O-tetradecanoylphorbol 13-acetate) were not suppressed when acini were exposed to FK506, suggesting that the cAMP-dependent protein kinase pathway and protein kinase C pathway were not affected by FK506. However, amylase release in response to calcium ionophore (4-bromo-A23187) was suppressed by FK506, whereas the increase in cytosolic free calcium concentration caused by 4-bromo-A23187 was not affected by FK506. These results suggest that FK506 suppressed secretagogue-stimulated amylase release in acini by altering Ca(++)-mediated intracellular pathways. Further, the property of CCK-8 binding site, CCK-8 stimulated inositol phosphates formation, rises in cytosolic free calcium concentration, and calcium efflux from acini were not suppressed by exposing acini to FK506. These findings indicate that FK506 suppresses amylase release by affecting postreceptor intracellular pathways that are mediated by Ca++ in stimulus secretion coupling.
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PMID:Biochemical characterization of the effects of FK506 on signal transduction in exocytotic function of rat pancreatic acini. 767 38

In dispersed acini from rat pancreas, verapamil (a phenylalkylamine calcium channel blocker) potentiated amylase secretion stimulated by vasoactive intestinal peptide (VIP), secretin, peptide histidine isoleucine, helodermin, forskolin, and 8-bromocyclic AMP. The action of verapamil on VIP-stimulated amylase secretion was detectable at 10 microM verapamil and maximal at 100 microM verapamil. Verapamil did not alter binding of 125I-VIP, basal cAMP, the increase in cAMP caused by VIP, or the increase in cAMP-dependent protein kinase caused by VIP. The effects of verapamil on stimulated amylase secretion were fully reversible and could be reproduced by nicardipine (a 1,4-dihydropyridine calcium channel blocker) and diltiazem (a benzothiazepine calcium channel blocker), but not by cinnarizine (a piperazine calcium channel blocker). Although 300 microM verapamil increased outflux of 45Ca, 100 microM verapamil, the concentration that produced maximal potentiation of VIP-stimulated amylase secretion, did not alter 45Ca outflux. Our results indicate that the action of verapamil to potentiate amylase secretion stimulated by secretagogues that activate the cAMP pathway occurs at a step that is distal to the activation of cAMP-dependent protein kinase.
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PMID:Effect of verapamil on the cyclic AMP-mediated pathway for amylase secretion in rat pancreatic acini. 768 80

Rat granulosa cell-derived insulin-like growth factor (IGF) binding proteins (BPs) have been found subject to biphasic dose-dependent regulation by FSH under in vitro circumstances. Since cAMP may play an intermediary role in FSH hormonal action, we have undertaken to characterize the A kinase-mediated regulation of the elaboration of IGFBPs by cultured rat granulosa cells. Treatment with increasing concentrations of prostaglandin E2 or choleragen, both established cAMP-generating agonists, produced biphasic dose-dependent regulation of the release of the major 28-29 kilodalton (kDa) IGFBP species while promoting the release of their minor 24 (and 19) kDa counterparts. Similar effects were noted for other cAMP-generating agonists including vasoactive intestinal peptide and forskolin (a potent activator of adenylate cyclase). Moreover, concomitant treatment with a functionally inert low dose (10(-7) M) of forskolin, substantially potentiated the FSH (10 ng/ml)-mediated inhibition of the elaboration of the 28-29 kDa IGFBPs. Application of decreasing dilutions of the invasive adenylate cyclase toxin of bordetella pertussis (but not of an inactive mutant strain) yielded monophasic dose-dependent modulation of the release of the 28-29 kDa IGFBPs while effecting biphasic regulation of the 24 kDa moiety. Concurrent treatment with 1-methyl-3-isobutylxanthine (a potent inhibitor of cAMP phosphodiesterase activity) at the 10(-4) M level resulted in profound (P < 0.05) inhibition of the (low dose) FSH (3 ng/ml)-supported accumulation of the major 28-29 kDa IGFBP species, an effect associated with modest (2.5-fold) induction (P < 0.05) of the minor 24 kDa IGFBP moiety. Lastly, provision of increasing concentrations of nondegradable lipophilic analogs of cAMP (i.e. (Bu)2cAMP and 8-bromoadenosine cAMP resulted in biphasic dose-dependent modulation of the release of the major 28-29 kDa IGFBP doublet while producing an increase in the accumulation of the minor 24 kDa IGFBP species. Taken together, these observations suggest that the ability of low dose FSH to stimulate and of high dose FSH to inhibit the elaboration of the 28-29 kDa IGFBP species may entail activation of the A-kinase transduction pathway. Similar conclusions appear to apply for the ability of FSH to regulate (albeit at a lower response sensitivity level) the biphasic elaboration of the 24 kDa IGFBP moiety. As such, these observations point out the disparate response sensitivities of distinct IGFBP species, thereby suggesting a novel potent mechanism through which FSH may determine the relative distribution pattern of granulosa cell-derived IGFBPs and the consequent overall IGF responsiveness of this cell type.
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PMID:A kinase-mediated regulation of granulosa cell-derived insulin-like growth factor binding proteins (IGFBPs): disparate response sensitivities of distinct IGFBP species. 768 61

Primary tracheal epithelial cells obtained from two fetuses with cystic fibrosis (CF) were successfully transfected with a plasmid vector recombined with the large T oncogene of SV40. The resulting tracheal cells were propagated in culture for up to 25 passages and retained the mutations of the CF genes carried by the two fetuses, one heterozygous for the S549N and N1303K substitutions (CFT-1 cells), and the other homozygous for the most common deletion delta F508 (CFT-2 cells). The transfected cells: (a) expressed the SV40 large T oncogene, as determined by immunofluorescence and Northern blot analysis; (b) retained typical epithelial morphology, as assessed by the presence of microvilli, desmosomes, gap junctions, and cytokeratin expression; (c) were fully responsive to the cAMP-stimulating agents isoproterenol, forskolin and vasoactive intestinal peptide for cAMP production and PKA activation; (d) do not produce any tumour in the athymic nude mice; (e) were diploid and tetraploid with a normal chromosomal complement at early passages, and (f) exhibited the abnormal regulation of chloride conductance characteristic of CF. These results indicate that CFT-1 and CFT-2 cells constitute a suitable model for: (a) comparison of the maturation and function of the CFTR protein mutated in the two nucleotide-binding domains; (2) analysis of the biochemical defect in CF epithelial airway cells, (c) development of new therapeutic agents, and correction of the CF defect by gene replacement therapy in vitro.
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PMID:Oncogene-mediated propagation of tracheal epithelial cells from two cystic fibrosis fetuses with different mutations. Characterization of CFT-1 and CFT-2 cells in culture. 768 54

In this study we analysed the involvement of the cAMP-protein kinase-A system in the regulation of interleukin 6 production by cultured cortical astrocytes. Vasoactive intestinal peptide strongly increased, in a dose-dependent manner, interleukin 6 production. This effect was reduced when protein kinase A was blocked by KT-5720; it was not affected by calphostin C, a protein kinase C inhibitor. Forskolin caused a concentration-dependent increase in interleukin 6 release, that was also inhibited by KT-5720. Since prostaglandins are believed to play a role in interleukin 6 production, we tried to determine whether the stimulatory effects of vasoactive intestinal peptide and forskolin on cytokine release might be mediated by stimulation of prostaglandin production in cortical astrocytes. Vasoactive intestinal peptide did not increase the production of either prostaglandin E2 or F2 alpha. Conversely, forskolin concentration-dependently stimulated the production of both prostaglandins, an effect that was blocked by indomethacin. Indomethacin did not affect either vasoactive intestinal peptide- or forskolin-stimulated interleukin 6 production. To exclude the possibility that prostaglandins participate in interleukin 6 production induced by forskolin, we tested the effect of prostaglandins E2 and F2 alpha on the cytokine production. The former was completely ineffective in eliciting the cytokine production, while prostaglandin F2 alpha slightly increase interleukin 6 only at the highest concentration. 8-Br-cAMP and (BU)2- cAMP stimulated interleukin 6 production to a lesser extent than vasoactive intestinal peptide and forskolin. In conclusion, we provide evidence that vasoactive intestinal peptide increases interleukin 6 production by astrocytes through the stimulation of the cAMP-protein kinase-A pathway, an effect that is reproduced by cAMP analogues. In addition, we point out that prostaglandins are not involved in vasoactive intestinal peptide- and forskolin-mediated induction of interleukin 6 production in cultured astrocytes.
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PMID:Regulation of interleukin 6 production by cAMP-protein kinase-A pathway in rat cortical astrocytes. 783 Nov 91

The signaling pathways mediating relaxation by vasoactive intestinal peptide (VIP), peptide histidine-isoleucine amide (PHI), isoproterenol (ISO), and sodium nitroprusside (SNP) were examined in dispersed rabbit and guinea pig gastric muscle cells. In rabbit muscle cells, SNP stimulated only guanosine 3',5'-cyclic monophosphate (cGMP) and cGMP-dependent protein kinase (cG-kinase) activity; VIP stimulated adenosine 3',5'-cyclic monophosphate (cAMP) and cGMP, and both cG-kinase and cAMP-dependent protein kinase (cA-kinase) activities; PHI and ISO stimulated only cAMP and cA-kinase activity, and at higher concentrations, cross-activated cG-kinase. All four agents elicited concentration-dependent relaxation. N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89; 1 microM) selectively inhibited cA-kinase activity and abolished relaxation when only cA-kinase was elevated. 8R,9S, 11S-(-)-9-methoxy-carbamyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy- 1H,8H,11H-2,7b,11a-trizadibenzo-(a,g)-cy-cloocta-(c,d,e)- trinden-1-one (KT-5823; 1 microM) selectively inhibited cG-kinase activity and abolished relaxation when only cG-kinase was elevated. When both kinases were elevated, H-89 and KT-5823 partially inhibited relaxation and abolished relaxation in combination. In permeabilized guinea pig and rabbit muscle cells, all agents elicited relaxation and inhibited inositol 1,4,5-trisphosphate (IP3)-induced Ca2+ release. Both functions were inhibited in parallel fashion by protein kinase inhibitor PKI(6-22) and by KT-5823. We conclude that cA-kinase and cG-kinase act separately and in concert to inhibit IP3-dependent Ca2+ release and induce relaxation.
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PMID:Interaction of cA-kinase and cG-kinase in mediating relaxation of dispersed smooth muscle cells. 784 Jan 45

Using an in vitro incubation system, the role of the cyclic AMP-dependent protein kinase A (PKA) pathway in the regulation of the in situ activity of tyrosine hydroxylase (TH) was studied in the hypothalamuses of young and aged ovariectomized rats. Hypothalamic tissue was incubated for 60 min in medium containing 3-hydroxybenzylhydrazine dihydrochloride, a dihydroxyphenylalanine (DOPA) decarboxylase inhibitor, and various agents that modify the activity of the PKA pathway. At the end of the incubation, the tissue was homogenized and analyzed for DOPA and TH mass. The in situ molar activity of TH was expressed as the moles of DOPA accumulating in the tissue per mole of TH per hour. Forskolin, an activator of adenylyl cyclase and the cyclic AMP agonist, (Sp)-cyclic adenosine 3',5'-monophosphothioate, significantly (P < .01) increased the in situ molar activity of TH in the hypothalamic dopaminergic (DAergic) neurons of both young and aged rats. Theophylline, a phosphodiesterase inhibitor, did not affect the TH molar activity in the hypothalamuses of aged animals but did significantly (P < .001) increase its activity in those of young rats. When vasoactive intestinal peptide was evaluated, the TH molar activity was significantly (P < .005) increased in the hypothalamuses of young rats but not in those of aged rats. It was suggested that the deficiency of DA secretion by hypothalamic DAergic neurons of aged rats may be the result of insufficient activation of PKA caused by failure of transduction of an extracellular signal to activate adenylyl cyclase and produce cyclic AMP.
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PMID:Localization of a defect in hypothalamic dopaminergic neurons of the aged brain that results in impaired PKA-dependent activation of tyrosine hydroxylase. 790 91

Pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) is a neuropeptide related to vasoactive intestinal peptide-secretin-glucagon which stimulates adenylate cyclase in cultured rat pituitary cells and stimulates LH and FSH release in vitro and in vivo. Because the cAMP-protein kinase-A pathway regulates the gonadotropin subunit messenger RNAs (mRNAs) and modulates GnRH-stimulated gonadotropin secretion in vitro, we examined the effects of PACAP38 on gonadotropin secretion and subunit mRNA levels. Anterior pituitary cells were prepared from 7-week-old male rats castrated at 5 weeks of age. In monolayer cultures stimulated with GnRH, 0.1-10 nM PACAP38 decreased (P < 0.05) the EC50 for GnRH dose-dependently without affecting the maximum LH secretory response. Cells were next stimulated with 1-min pulses of 2.5 nM GnRH every hour for 9 h in the absence or presence of 10 nM PACAP38, which was perifused continuously. The amplitude of GnRH-induced LH, FSH, and alpha-subunit secretory episodes from PACAP38-treated cells rose (P < 0.01) gradually to 233 +/- 54%, 197 +/- 44%, and 378 +/- 104%, respectively (mean +/- SEM; n = 5 experiments), of the value for control cells lacking PACAP38. This enhancement was sustained for at least 3 h after PACAP38 was removed from the perifusion medium. With PACAP treatment, interpulse secretion of LH and alpha-subunit increased gradually (P < 0.01) to 174 +/- 21% and 212 +/- 64% of the value for chambers stimulated with GnRH alone (control), respectively, whereas interpulse secretion of FSH declined (P < 0.001) to 75 +/- 7% of the control value. In contrast to the gradual effect of PACAP38 to enhance GnRH-induced hormone secretion, PACAP38 alone produced a transient burst of gonadotropin secretion. At the completion of the perifusions, total RNA was extracted and gonadotropin subunit mRNA levels were determined by Northern analysis. GnRH increased (P < 0.01) FSH beta mRNA to 438 +/- 52% of the level in cells stimulated with medium alone (control). Adding PACAP38 to the perifusion medium partially blocked (P < 0.01) the effect of GnRH (178 +/- 20% of the control value), and PACAP38 alone reduced (P < 0.01) FSH beta mRNA levels to 31 +/- 3% of the control value. By contrast, alpha-subunit mRNA levels were increased by both PACAP38 (143 +/- 4% of the control value; P < 0.01) and GnRH (121 +/- 2% of the control value; P < 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of pituitary adenylate cyclase-activating polypeptide on gonadotropin secretion and subunit messenger ribonucleic acids in perifused rat pituitary cells. 791 30

The gamma-aminobutyric acid type A (GABAA) receptor is the predominant Cl(-)-channel protein mediating inhibition in the retina and elsewhere in the mammalian brain. We have observed a time-dependent increase of GABA-induced whole-cell currents when dopamine was applied externally to rat retinal amacrine cells. After 20 min, the peak current was increased to 208% +/- 10% of its initial value. A comparable effect was observed with the dopamine D1 receptor agonist (+)-1-phenyl-2,3,4,5-tetrahydro(1H)-3-benzazepine-7,8-diol hydrochloride (SKF-38393) but not with the D2 agonist bromocryptine. The action of dopamine involved phosphorylation of GABAA receptors by protein kinase A, as evident from intracellular application of protein kinase A, cAMP, and forskolin. Both guanosine 5'-[gamma-thio]triphosphate and cholera toxin augmented the GABA response, indicating a role for the guanosine 5'-triphosphate-binding protein Gs in the transduction cascade. Phosphorylation of GABAA receptors shifted the half-maximally effective GABA concentration from 71 microM to 47 microM without affecting the maximal response amplitude. The elevated binding affinity for GABA was caused by an increase of the open probability of the channels from 0.09 to 0.33 (2 microM GABA); conductance and mean open time did not change. Several other receptor agonists such as adenosine, histamine, somatostatin, enkephalin, and vasoactive intestinal peptide were found to couple to the same intracellular phosphorylation pathway. Since some of these cotransmitters colocalize with GABA in amacrine cells, they may fine-tune GABAergic inhibition in the retina.
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PMID:Facilitation of GABAergic signaling in the retina by receptors stimulating adenylate cyclase. 797 79


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