Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sustained smooth muscle contraction is mediated by protein kinase C (PKC) through a signal transduction cascade leading to contraction. Heat-shock protein 27 (HSP27) appears to be the link between these two major events, i.e., signal transduction and sustained smooth muscle contraction. We have investigated the involvement of HSP27 in signal transduction and HSP27 association with contractile proteins (e.g., actin, myosin, tropomyosin, and caldesmon) resulting in sustained smooth muscle contraction. We have carried out confocal microscopy to investigate the cellular reorganization and colocalization of proteins and immunoprecipitation of HSP27 with actin, myosin, tropomyosin, and caldesmon as detected by sequential immunoblotting. Our results indicate that 1) translocation of Raf-1 to the membrane when stimulated with ceramide is inhibited by vasoactive intestinal peptide (VIP), a relaxant neuropeptide; 2) PKC-alpha and mitogen-activated protein kinase translocate and colocalize on the membrane in response to ceramide, and PKC-alpha translocation is inhibited by VIP; 3) HSP27 colocalizes with actin when contraction occurs; and 4) HSP27 immunoprecipitates with actin and with the contractile proteins myosin, tropomyosin, and caldesmon. We propose a model in which HSP27 is involved in sustained smooth muscle contraction and modulates the interaction of actin, myosin, tropomyosin, and caldesmon.
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PMID:HSP27 in signal transduction and association with contractile proteins in smooth muscle cells. 1044 59

We studied the modes of activation of the salt-secreting rectal gland of the spiny dogfish, Squalus acanthias, by the native cardiac peptide CNP. The stimulatory action of CNP in isolated perfused glands is inhibited by 10 mM procaine, presumably by blocking release of vasoactive intestinal peptide (VIP) from nerves. Procaine reduces the slope of the dose-response curve of human CNP and that of shark CNP (each P < 0.0001). CNP increases short-circuit current in cultured rectal gland cells from 4.8 +/- 1.6 to 27.0 +/- 7.8 microA/cm2. It also stimulates the secretion of chloride in isolated perfused glands in the presence of 10 mM procaine from 72 +/- 31 to 652 +/- 173 microeq. h(-1). g(-1). These results suggest that CNP has a direct cellular action not mediated by the neural release of VIP. The residual stimulation of perfused glands in the presence of procaine was almost completely inhibited by staurosporine [10 nM; an inhibitor of protein kinase C (PKC)] from 652 +/- 173 to 237 +/- 61 microeq. h(-1). g(-1). Although CNP stimulates guanylyl cyclase in shark rectal gland, chloride secretion of perfused glands was not elicited by 8-bromoadenosine-cGMP (8-BrcGMP) alone nor by the activator of PKC phorbol ester. The combination of PKC activation and 8-BrcGMP infusion, however, stimulated chloride secretion in perfused glands from 94 +/- 30 to 506 +/- 61 microeq. h(-1). g(-1), a level comparable to that observed in glands blocked with procaine. Several parallel pathways appear to be synergistic in activating chloride secretion stimulated by CNP in the rectal gland.
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PMID:Mode of activation of salt secretion by C-type natriuretic peptide in the shark rectal gland. 1060 Sep 20

Intracerebral administration of the excitotoxin ibotenate to new-born mice induced white-matter lesions mimicking the periventricular leukomalacia occurring in human premature babies. In this model, co-injection of vasoactive intestinal peptide (VIP) prevented white-matter lesions. VIP did not prevent the initial appearance of white-matter lesion, but promoted a secondary repair with axonal regrowth. Co-administration of ibotenate, VIP, and transduction inhibitors showed that protein kinase C (PKC) and mitogen-associated protein kinase (MAPK) pathways were critical for neuroprotection. The combination of in vitro and in vivo studies suggested the following model: VIP activates PKC in astrocytes, which release soluble factors; these released factors activate neuronal MAPK and PKC, which will permit axonal regrowth. Previous studies had shown that VIP-treated cultured astrocytes release growth factors including activity-dependent neurotrophic factor (ADNF) and that a 14-amino-acid peptide derived from ADNF protected the developing white matter against ibotenate. However, co-treatment with ibotenate, VIP, and anti-ADNF antibodies did not abolish VIP-induced protection, suggesting that ADNF does not mediate VIP protective properties in the present model.
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PMID:VIP neuroprotection against excitotoxic lesions of the developing mouse brain. 1067 40

Secretin, glucagon, gastric inhibitory polypeptide (GIP), and parathyroid hormone (PTH) belong, together with vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase (AC)-activating polypeptide, to a family of peptides (the VIP-secretin-glucagon family), which also includes growth hormone-releasing hormone and exendins. All the members of this peptide family possess a remarkable amino-acid sequence homology, and bind to G-protein-coupled receptors, whose signaling mechanism primarily involves AC/protein kinase A and phospholipase C/protein kinase C cascades. VIP and pituitary AC-activating polypeptide play a role in the regulation of the hypothalamus-pituitary-adrenal (HPA) axis, and in this review we survey findings that also other members of the VIP-secretin-glucagon family may have the same function. Secretin and secretin receptors are expressed in the hypothalamus and pituitary gland, and secretin inhibits adrenocorticotropic hormone (ACTH) release. No evidence is available for the presence of secretin receptors in adrenal glands, but secretin selectively depresses the glucocorticoid response to ACTH of dispersed zona fasciculata-reticularis (ZF/R) cells. Glucagon and glucagon-like peptide-1 are contained in the hypothalamus, and all the components of the HPA axis are provided with glucagon and glucagons-like-1 receptors. These peptides exert a short-term inhibitory effect on stress-induced pituitary ACTH release and depress the ZF/R cell response to ACTH by inhibiting the AC/protein kinase A cascade; they also stimulate hypothalamic arginine-vasopressin release. GIP receptors are present in the ZF/R of the normal adrenals, and are particularly abundant in some types of adrenocortical adenomas and hyperplasias. GIP, through the activation of the AC/protein kinase A cascade, evokes a sizeable glucocorticoid secretagogue effect, leading to the identification of a food/GIP-dependent Cushing's syndrome. PTH and PTH-related protein are expressed in the hypothalamus and pituitary gland, and PTH and PTH-related protein receptors in all the components of the HPA axis. Both peptides enhance ACTH and arginine-vasopressin release, as well as stimulate aldosterone and glucocorticoid secretion of dispersed zona glomerulosa and ZF/R cells, respectively. The involvement of growth hormone-releasing hormone and exendins in the functional regulation of the HPA axis has not yet been extensively investigated.
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PMID:Secretin, glucagon, gastric inhibitory polypeptide, parathyroid hormone, and related peptides in the regulation of the hypothalamus- pituitary-adrenal axis. 1076 61

Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP38) regulate anterior pituitary cell secretion and proliferation. In the somatolactotrope GH4C1 cell line, these effects are mediated through the type-II-like PACAP receptor (VPAC2) coupled to the cAMP pathway. In this study, the control of the extracellularly responsive kinases (ERKs) by VIP and PACAP38 was investigated in GH4C1 cells. VIP and PACAP38 increased ERK1 and ERK2 phosphorylation and were equipotent stimulators of both kinases. ERK activation was mimicked by cholera toxin, forskolin and 8bromo-cAMP. VIP and PACAP38 activation of ERK2 was blocked by the protein kinase A inhibitor H89, whereas the protein kinase C inhibitor GF109203X, or prior PMA-induced depletion of the protein kinases C, failed to inhibit VIP and PACAP38 activation of ERK2. In contrast, thyrotropin-releasing hormone (TRH) elicited ERK activation by a PKC-dependent process. ERK activation by VIP or PACAP38 and TRH were additive and both sensitive to the MEK inhibitors PD98059 and U0126. In parallel, U0126 reduced prolactin (PRL) mRNA levels induced by VIP. These results demonstrate for the first time that VIP and PACAP38 activate ERK in GH4C1 cells. Cyclic AMP increase is sufficient to elicit ERK activation in these cells and thus likely to represent the transduction pathway underlying VIP- and PACAP38-dependent ERK activation. This mechanism seems to be involved in VIP-induced PRL gene regulation.
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PMID:Vasoactive intestinal polypeptide and pituitary adenylate cyclase-activating polypeptides stimulate mitogen-activated protein kinase in the pituitary cell line GH4C1 by a 3',5'-cyclic adenosine monophosphate pathway. 1094 Jul 38

To investigate the influence of vasoactive intestinal peptide (VIP) on chemotaxis of bronchial epithelial cells (BECs). Rabbit chemotactic migration of primary BEC was assessed in a blind-well Boyden chamber. Radioimmunoassay and radio-ligand affinity analysis were used for determining VIP secretion and vasoactive intestinal peptide receptor (VIPR) expression. The results showed: (1) the method for determining chemotaxis of BECs by using insulin as chemotactic factor was stable and reproducible (r=0.9703, P<0.01). (2) VIP (0.001-1 micromol/L) elicited chemotaxis of BECs which was substantial and concentration-dependent. The effects of VIP were inhibited by W-7 and H-7 (P<0.01). (3) Heat stress enhanced the secretion of VIP (P<0.01) and upregulated the expression of VIPR on BECs (P<0.05). These results indicate that VIP in the lungs may play an important role in the repair of damaged epithelium, accelerating restoration of the airway to its normal state. Calmodulin and protein kinase C may be involved in the signal transduction of VIP effects.
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PMID:[Effects of vasoactive intestinal peptide on chemotaxis of bronchial epithelial cells]. 1197 86

Pituitary adenylate cyclase-activating polypeptide (PACAP38) and vasoactive intestinal peptide (VIP) were tested for their ability to influence protein kinase C (PKC) activity in the chick cerebral cortical slices. Thirty minutes incubation of the chick tissue with PACAP38 (0.1-1 microM) or VIP (0.3-3 microM) produced significant and concentration-dependent changes in PKC activity. Both peptides enhanced the enzyme activity in cell membrane preparation, and decreased it in cytosol preparation obtained from cerebral cortical slices. These changes in PKC activity suggest that PACAP and VIP are capable of activating this enzyme in cerebral cortex of chick.
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PMID:Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) activate protein kinase C in chick cerebral cortex. 1198 49

The VPAC1 receptor for vasoactive intestinal peptide (VIP) belongs to the class II family of G protein-coupled receptors and is coupled to Gs protein/adenylyl cyclase. We assessed whether 10 different Ser/Thr residues in human VPAC1 receptor intracellular domains play a role in the process of VIP-induced desensitization/internalization by performing a site-directed mutagenesis study. The Ser/Thr residues mutated to Ala include potential G protein-coupled receptor kinase, protein kinase A and protein kinase C targets that are of particular interest for VPAC1 receptor desensitization. The data show that when Chinese hamster ovary cells expressing wild-type receptors were pretreated for 5 min with VIP (50 nM), receptor desensitization occurred with a 10-fold right shift of the ED50 for adenylyl cyclase activation. When the construct with the widest span of mutations was studied, there was no longer any short-term desensitization. By using constructs with fewer and fewer mutations, we identified Ser447 in the C-terminal tail to be crucial for rapid desensitization. We also showed that Ser447 plays an essential role for VIP-induced VPAC1 phosphorylation in Chinese hamster ovary cells. Furthermore, we demonstrated that none of the mutated Ser/Thr residues was involved in down-regulation after a 12-h treatment of cells with 50 nM VIP. Neither were they involved in VIP and VIP-induced receptor internalization as shown using a novel fluorescein-tagged VIP and VPAC1 receptor bearing a Flag epitope in the N-terminal domain and a green fluorescent protein at the C terminus. We conclude that Ser447, a likely G protein-coupled receptor kinase target, is crucial for VIP-induced phosphorylation and rapid desensitization of VPAC1 receptor.
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PMID:Serine 447 in the carboxyl tail of human VPAC1 receptor is crucial for agonist-induced desensitization but not internalization of the receptor. 1464 88

In recent years, it has become evident that neural stem cells in the adult mammalian brain continuously generate new neurons, mainly in the hippocampus and olfactory bulb. Although different growth factors have been shown to stimulate neurogenesis in the adult brain, very little is known about the role of neuropeptides in this process. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with pleiotropic effects acting through three receptors to which it has high affinity, namely, PACAP receptor 1 (PAC1), vasoactive intestinal peptide (VIP) receptor 1, and VIP receptor 2. We show that PAC1 is expressed in the neurogenic regions of the adult mouse brain, namely the ventricular zone of the lateral ventricle and the hippocampal dentate gyrus. Cultured neural stem cells isolated from the lateral ventricle wall of adult mice express PAC1 and proliferate in vitro in response to two PAC1 agonists, PACAP and Maxadilan, but not VIP at physiologic concentrations, indicating PAC1 as a mediator of neural stem cell proliferation. Pharmacologic and biochemical characterization of PACAP-induced neural stem cell proliferation revealed the protein kinase C pathway as the principal signaling pathway, whereas addition of epidermal growth factor synergistically enhanced the proliferating effect of PACAP. Further in vitro characterization of the effect of PACAP on neural stem cells showed PACAP capable of stimulating ex novo in vitro formation of multipotent neurospheres with the capacity to generate both neuronal and glial cells. Finally, intracerebroventricular infusion of PACAP increases cell proliferation in the ventricular zone of the lateral ventricle and the dentate gyrus of the hippocampus. We conclude that PACAP, through PAC1, is a potent mediator of adult neural stem cell proliferation.
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PMID:PACAP promotes neural stem cell proliferation in adult mouse brain. 1504 18

The Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two novel neuropeptides which produce particular biological effects caused by interaction with G-protein-coupled receptors. We have shown in a previous study where VIP and PACAP 38 inhibit voltage-dependent calcium channel (VDCC) currents (ICa) via G-proteins in hamster submandibular ganglion (SMG) neurons. In this study, we attempt to further characterize the signal transduction pathways of VIP-and PACAP 38-induced modulation of ICa. Application of 1 microM VIP and PACAP 38 inhibited ICa by 33.0 +/- 3.1% and 36.8 +/- 2.6%, respectively (mean +/- S.E.M., n = 8). Application of strong voltage prepulse attenuated PACAP 38-induced inhibition of ICa. Pretreatment of cAMP dependent protein kinase (PKA) activator attenuated VIP-induced inhibition, but not the PACAP 38-induced inhibition. Intracellular dialysis of the PKA inhibitor attenuated the VIP-induced inhibition, but not the PACAP 38-induced inhibition. Pretreatment of protein kinase C (PKC) activator and inhibitor attenuated VIP-induced inhibition, but not the PACAP 38-induced inhibition. Pretreatment of cholera toxin (CTX) attenuated PACAP 38-induced inhibition of ICa. These findings indicate that there are multiple signaling pathways in VIP and PACAP 38-induced inhibitions of ICa: one pathway would be the VPAC1/VPAC2 receptors-induced inhibition involving both the PKA and PKC, and another one concerns the PAC1 receptor-induced inhibition via Gs-protein betagamma subunits. The VIP-and PACAP 38-induced facilitation of ICa can be observed in the SMG neurons in addition to inhibiting of ICa.
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PMID:Multiple signal pathways coupling VIP and PACAP receptors to calcium channels in hamster submandibular ganglion neurons. 1510 35


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