Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The effect of a cAMP-dependent secretogogue (VIP) on the phosphorylation of an endogenous, membrane-bound protein (pp170) was assessed in an intact cell preparation from the avian salt gland. The addition of VIP, in the presence of 100 microM isobutylmethylxanthine, resulted in a concentration-dependent increase in phosphorylation of pp170. This effect was rapid and transient with a 3-5-fold increase in phosphorylation occurring 1 min after the addition of VIP. Under similar incubation conditions, VIP stimulated a 4.6-fold increase in cAMP accumulation that paralleled phosphorylation. Exposure of cells to either forskolin or 8-Br-cAMP resulted in a 5-8-fold increase in the phosphorylation of pp170. The effect of forskolin was dose dependent with an EC50 similar to that for stimulation of secretion (35 nM). These results implicate an involvement for a cAMP-dependent protein kinase in the phosphorylation of pp170. The identity of pp170 was assessed utilizing a monoclonal antibody (Q3) directed against pp170. Q3 recognized a single 170-kDa band on Western blots of salt gland membrane protein. Immunoprecipitation of pp170 from salt gland cells resulted in the selective extraction of a single protein whose phosphorylation state was increased approximately 5-fold in response to carbachol or VIP. The identity of pp170 was established using two criteria. First, Q3 recognized affinity-purified Na:K:Cl cotransporter preparations from shark rectal gland membranes. Second, pp170 was selectively immunoprecipitated by monoclonal antibodies (J3, J4, and J7) that recognize different epitopes of the shark transport protein. These results suggest that pp170 is homologous to the shark rectal gland Na-K-Cl cotransporter, and thus the proteins may be functionally similar.
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PMID:The Na-K-Cl cotransporter of avian salt gland. Phosphorylation in response to cAMP-dependent and calcium-dependent secretogogues. 128 Nov 59

We have reviewed the literature, which supports an important role for dopamine withdrawal in the regulation of PRL secretion. Concentrations of dopamine in the hypophyseal portal circulation are sufficient to occupy the majority of dopamine receptors (1) and tonically suppress PRL secretion (20-26). Brief escapes from dopaminergic regulation associated with the secretion of PRL have been observed (37-41). Therefore, dopamine regulates secretion of PRL both by occupancy of, as well as dissociation from, specific D2 dopamine receptors. The rapid off rate from its receptor (2) is consistent with signals transmitted through brief decreases in dopamine concentration. The removal of dopamine for 10 min results in increases in intracellular cAMP and presumably activation of protein kinase A (39, 138) as well as activation of phospholipase C (137, 138) and protein kinase C (136). The removal of dopamine results directly in the release of PRL (37-41). Furthermore, the brief removal of dopamine results in the long-term potentiation of the PRL-releasing action of TRH (38-40). The potentiating action of dopamine withdrawal appears to be mediated by the activation of protein kinase A since pretreatment with VIP, a hormone that signals via protein kinase A, also potentiates the action of TRH (39). TRH stimulates PRL release via Ca2+/protein kinase C (177-184). The potentiating action of dopamine removal is selective for the Ca2+/protein kinase C pathway since dopamine removal does not potentiate the PRL-secreting action of VIP (38, 87, 92). The action of TRH is potentiated up to 30 min after the return of dopamine and the suppression of PRL to basal levels (38). In Fig. 10, dopamine dissociation from its receptor or VIP association to its receptor are shown separated by a broken line to indicate that by the time the potentiation of the action of TRH is tested, either dopamine is again occupying its receptor or VIP is no longer present. Therefore, the effect of protein kinase A activation is remembered by the lactotroph. We hypothesize that the responsiveness of the cell to TRH is potentiated by the phosphorylation of proteins by protein kinase A. Two potential substrates for protein kinase A are voltage-dependent Ca2+ channels and protein phosphatase inhibitors that would prolong the action of protein kinase C. When TRH occupies its receptor, intracellular Ca2+ levels are increased first from intracellular stores and subsequently by extracellular Ca2+ influx (187-189). Intracellular Ca2+ is mobilized by increased levels of IP3(128). Extracellular Ca2+ enters the lactotroph via voltage-dependent Ca2+ channels (189, 190).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Dissociation of dopamine from its receptor as a signal in the pleiotropic hypothalamic regulation of prolactin secretion. 161 63

Secretion of beta-endorphin from mouse pituitary AtT20 cells is stimulated by a variety of compounds that raise intracellular cAMP and Ca2+. To investigate the role of cAMP-dependent protein kinases in secretion, AtT20 cells were transfected with an expression vector coding for a regulatory (R) subunit of cAMP-dependent protein kinase containing mutations in both cAMP-binding sites. Expression of the mutant regulatory subunit in stable transformants (RAB cells) results in a dominant inhibition of cAMP-dependent protein kinase activity. Isoproterenol (1 microM) or analogs of cAMP stimulated beta-endorphin secretion from AtT20 cells, but failed to stimulate secretion in RAB cells expressing the mutant R subunit. Secretion in response to CRF (100 nM) was inhibited by 80% in these mutant clones, whereas the secretory response to vasoactive intestinal peptide (VIP; 100 nM) or phorbol ester (100 nM phorbol myristate acetate) was not inhibited by the R subunit mutation. Intracellular cAMP was elevated in response to CRF (11- to 15-fold), isoproterenol (5- to 10-fold), and VIP (4- to 8-fold) in RAB cells. Similar concentrations of VIP were required to evoke beta-endorphin secretion in either RAB cells or AtT20 cells. As with most secretagogues, VIP-induced secretion was inhibited in the presence of either EGTA or a voltage-sensitive Ca2+ channel antagonist, PN200-110. The secretory response to VIP was unaffected by down-regulation of protein kinase-C. These results suggest that CRF and isoproterenol work via cAMP-dependent protein kinase to activate beta-endorphin secretion, whereas VIP can act by a different mechanism that does not involve cAMP-dependent protein kinase or protein kinase-C.
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PMID:Role of cyclic adenosine 3',5'-monophosphate-dependent protein kinase in hormone-stimulated beta-endorphin secretion in AtT20 cells. 164 51

Cyclic adenosine monophosphate (cAMP)-mediated signal transduction was evaluated in synaptosomes prepared from rat brain cortex. Adenylate cyclase was responsive to known adenylate cyclase stimulators including peptides (CRH and VIP), catecholamines (norepinephrine and isoproterenol) and ligands that directly stimulate adenylate cyclase (forskolin). Cyclic AMP accumulation also increased approximately 2 to 3-fold, but none of the agonists was able significantly to activate cyclic AMP-dependent protein kinase (A-kinase) in cortical synaptosomes. However, in parallel studies with slices prepared from rat brain cortex, adenylate cyclase activity, cAMP accumulation and A-kinase activity were all stimulated by CRH, VIP, norepinephrine, isoproterenol and forskolin. These data suggest that, in intact synaptosomes, either the cellular machinery which facilitates binding of cAMP to the regulatory subunit of A-kinase is missing or the cAMP produced by adenylate cyclase is not accessible to A-kinase.
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PMID:Evidence that metabolically active synaptosomes lack functional cyclic AMP-dependent protein kinase. 176 Feb 53

Several protein kinases that copurify with neurofilaments (NF) were identified and each kinase was assessed for its ability to phosphorylate NF proteins. NFs were isolated using an axonal flotation procedure and the kinases were extracted from NFs with 0.8 M KCl. NF kinases were incubated with peptide substrates for selected protein kinases, [32P]ATP and protein kinase cofactors and inhibitors to characterize the kinases. Using peptide substrates, three types of kinase were identified, and a fourth was identified using NF protein as substrate. The first three kinases were the catalytic subunit of cAMP-dependent protein kinase, calcium-calmodulin dependent protein kinase II and a cofactor-independent kinase that phosphorylated prepro VIP sequence 156-170 and was inhibited by heparin. Using NF proteins as substrate, a fourth kinase was identified which was cofactor-independent and was not inhibited by heparin. Neither cofactor-independent kinase was casein kinase II. NF proteins were phosphorylated in vitro on serine and threonine, primarily by the two cofactor-independent kinases. Using [alpha-32P]8-N3ATP for affinity labeling, one kinase of 43,800 Da was identified. Thus, in addition to cAMP-dependent protein kinase and calcium-calmodulin dependent protein kinase II, two kinases have been found which are primarily responsible for NF phosphorylation in vitro and are cofactor-independent.
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PMID:Properties of several protein kinases that copurify with rat spinal cord neurofilaments. 275 40

In this study we have characterized and compared the regulation of the HT29 cell vasoactive intestinal peptide receptor/adenylate cyclase system (VIP-R/AC) by the VIP-R agonist peptide histidineisoleucineamide (PHI) and by activators of protein kinase C (PKC) including phorbol 12-myristate, 13-acetate (PMA) and mezerein. Preincubation with either PHI or PKC activator decreased maximum VIP-stimulated AC activity and decreased the number of cell surface VIP-R. A [125I]VIP binding assay using solubilized VIP-R of the plasma membrane and light vesicle fractions from sucrose density step gradients was developed as a more direct measure of VIP-R internalization. Preincubation with PHI or PMA decreased plasma membrane fraction [125I]VIP binding and increased binding in the light vesicle fraction, thus providing the most direct evidence to date for translocation of VIP-R per se from the plasma membrane to another, presumably intracellular, compartment. Two experimental approaches differentiated between agonist and PKC activator regulation of VIP-R/AC. The protein kinase inhibitors H-7 and staurosporine blocked mezerein-, but not PHI-, induced losses of cell surface VIP-R. Also, down-regulation of PKC did not block PHI-induced loss of cell surface VIP-R. Thus, although both agonist and PKC activators can lead to desensitization and internalization of VIP-R, PKC is apparently not involved in the mechanisms of agonist-induced desensitization.
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PMID:Vasoactive intestinal peptide receptor/adenylate cyclase system: differences between agonist- and protein kinase C-mediated desensitization and further evidence for receptor internalization. 284 20

The interaction between two neuropeptides, VIP and TRH, was studied. The TRH receptor binding ability was examined using intact GH3 cells and its membrane fraction. The TRH binding ability decreased when intact cells were preincubated with VIP, forskolin or db-cAMP, but not when the membrane fraction was treated with these agents. The binding was reduced only when the membrane fraction was treated with catalytic subunit of cAMP dependent protein kinase (A-kinase). These results indicate that the binding ability of TRH receptors, which are linked to inositol phospholipid metabolism, is suppressed when A-kinase increases due to activation of the adenylate cyclase or its dependent system. This, in turn, suggests the presence of a communication via a cytoplasmic factor (probably A-kinase) between the two principal second messenger systems in the cell.
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PMID:Receptor-stimulated system mediated interactions of neuropeptides in GH3 cells. 285 60

We used liposomes made with phospholipids of fatty acid chain length ranging from C12:0 to C16:0 to modify the cAMP dependent protein kinase (PK) activity of HT 29 cells induced by VIP or forskolin. Both VIP and forskolin effects were inhibited in dilauroylphosphatidylcholine (DLPC) treated cells. PK activity was slightly lowered when cells were treated by dimyristoylphosphatidylcholine (DMPC) liposomes. However neither VIP nor forskolin-induced PK activities were affected with dipalmitoylphosphatidylcholine (DPPC) liposomes. Furthermore, the binding of [125I]VIP to DLPC treated cells was drastically lowered whereas no change was observed when cells were incubated with DMPC or DPPC liposomes. On the other hand, the interaction of HT 29 cells with DLPC vesicles provoked a decrease in membrane cholesterol content with subsequent increase in membrane fluidity. These findings provide evidence that, in HT 29 cells, the mechanisms of VIP-receptor interaction and of adenylate cyclase activation is lipid dependent and is regulated by membrane fluidity.
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PMID:Modification of HT 29 cell response to the vasoactive intestinal peptide (VIP) by membrane fluidization. 300 97

Enkephalins, vasoactive intestinal polypeptide, and chromogranin A are all contained in the secretory vesicles of chromaffin cells in culture, and are all released from this compartment by secretagogues in a calcium-dependent way. The biosynthesis of each of these peptides, however, is under quite independent regulation. The synthesis and secretion of enkephalin is tightly coupled to acetylcholine and elevated potassium stimulation by calcium influx. Once calcium enters the cell, calcium acts at pharmacologically distinct sites to elicit secretion and enhanced biosynthesis of Metenkephalin. This is demonstrated by the calcium-independent stimulation of enkephalin secretion by 1 mM barium, in contrast to the dependence on extracellular calcium of barium-stimulated biosynthesis of this peptide. The synthesis and secretion of VIP is also coupled to acetylcholine and elevated potassium stimulation by calcium influx. Treatment with barium demonstrates that calcium acts at distinct sites to stimulate secretion and biosynthesis of this peptide; however induction of VIP by barium and veratridine shows greater sensitivity to the calcium channel blocker methoxyverapamil (D600) than does the induction of Met-enkephalin by these agents. These differences in D600 sensitivity may be due to differences in calcium metabolism or voltage-dependent calcium channels in enkephalin-producing and VIP-inducible subpopulations of chromaffin cells. Chromogranin A levels are essentially unaffected by any of the agents which increase enkephalin and VIP levels, although it is secreted in parallel with enkephalins and catecholamines from chromaffin cells in response to secretagogues. We suggest that peptide hormones such as VIP and enkephalins are regulated by calcium-dependent stimulus-secretion-synthesis coupling in the chromaffin cell. Cyclic AMP is a positive regulator of enkephalin and VIP biosynthesis, but does not affect acute release of these peptides. The cAMP/protein kinase A system may be a distal mediator of peptide biosynthesis stimulated by secretagogues. Alternatively, cAMP may be involved in early developmental establishment of phenotype or long-term regulation of peptide biosynthesis by other hormones or neurotransmitters. Chromogranin A may represent a class of intravesicular, soluble proteins that are expressed constitutively by the chromaffin cell in the presence or absence of positive regulators of other systems. The biosynthesis of chromogranin A may be coupled to the production or assembly of the secretory vesicle itself.
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PMID:Regulation of enkephalin, VIP, and chromogranin biosynthesis in actively secreting chromaffin cells. Multiple strategies for multiple peptides. 303 84

Figure 4 summarizes the steps by which Ca2+ and cyclic AMP-mediated secretagogues activate enzyme secretion in the pancreatic acinar cell. CCK and acetylcholine bind to specific plasma membrane receptors and through an as yet incompletely understood mechanism give rise to an elevation in free cytoplasmic Ca2+. A question central to this scheme is whether receptor binding leads to intracellular Ca2+ mobilization through generation of a diffusable mediator. Clues to answering this question may come from a) determining whether Ca2+ is released from the plasma membrane in addition to one or more intracellular organelles, and b) examining the role (if any) of membrane phosphatidylinositol metabolism in Ca2+ mobilization. A second class of secretagogues, represented by VIP and secretin, bind to their specific receptors and cause the accumulation of cyclic AMP. Cyclic AMP potentiates Ca2+ in activating secretion, and in some species, cyclic AMP may activate secretion independently of Ca2+. Ca2+ may act by regulating the activity of calmodulin dependent protein kinase(s) and phosphatase(s) and a phospholipid dependent kinase (protein kinase C) which has also been shown to be activated by diacylglycerol; cyclic AMP activates a distinct kinase termed protein kinase A. These kinases and phosphatases then alter the phosphorylation of specific proteins which are presumed to play structural or regulatory roles in exocytosis. Potentiation may thus result from interaction of Ca2+ and cyclic AMP at the level of a protein kinase, phosphatase or protein substrate.
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PMID:Stimulus-secretion coupling in pancreatic acinar cells. 609 80


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