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

1. Phorbol esters are known to inhibit phospholipase C-mediated hydrolysis of membrane phosphoinositide. This inhibition is attributed to participation of protein kinase C (PKC) in a negative-feedback control of phosphoinositide metabolism. We have tested this hypothesis by using different types of activators and inhibitors of PKC. 2. Phorbol-12,13-dibutyrate (PDB) inhibited the stimulatory effect of acetylcholine (ACh) on [3H]inositol monophosphate ([3H]IP) formation in cultured sympathetic neurons of the chick embryo and adrenal medulla of the rat. 3. Acetylcholine (ACh) and 5-hydroxytryptamine (5-HT) activated neuronal PKC by 3- to 8-fold. The extent of PKC activation by 100 microM-ACh was comparable to that of 100 nM-PDB. Activation of PKC by pre-incubation of sympathetic neurons with ACh (or 5-HT) did not inhibit the stimulatory effects of ACh (or 5-HT) on [3H]IP formation. 4. Pre-treatment of sympathetic neurons or adrenal medulla with a PKC inhibitor H7 (1-(5-isoquinolinyl-sulphonyl)-2-methyl-piperazine) almost completely blocked activation of the enzyme induced by PDB, ACh or 5-HT. However, blockade of PKC did not prevent the inhibitory effects of PDB on ACh-induced [3H]IP formation. 5. Vasoactive intestinal polypeptide (VIP) and muscarine induced catecholamine secretion from the perfused adrenal medulla via formation of inositol-1,4,5-tirisphosphate (IP3). Phorbol-12,13-dibutyrate decreased muscarine-induced catecholamine secretion. However, activation of PKC by VIP had no effect on muscarine-induced catecholamine secretion and vice versa. 6. These results suggest that PKC is not negatively coupled to phosphoinositide hydrolysis in sympathetic neurons and chromaffin cells. Phorbol esters must have targets other than PKC to interfere with the phosphoinositide hydrolysis.
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PMID:Phosphoinositide hydrolysis is not negatively regulated by protein kinase C in the peripheral tissues of rat and chick. 217 Jun 29

Regulation of active K+ influx and Na(+)-K(+)-Cl- cotransport activity in HT-29 cells by vasoactive intestinal peptide (VIP) was investigated. Both active K+ influx, defined as the ouabain-sensitive component, and Na(+)-K(+)-Cl- cotransport, defined as the ouabain-resistant bumetanide-sensitive component, of total K+ uptake were increased by VIP. VIP increased the maximum velocity (Vmax) values for both components with no change in apparent Michaelis constant (Km) values. Three lines of evidence support the role of adenosine 3',5'-cyclic monophosphate (cAMP) as a mediator of the VIP effects. 1) The rank order potencies of VIP and peptide histidineisoleucineamide (PHI) in binding and cAMP production (J. T. Turner, S. B. Jones, and D. B. Bylund, Peptides Fayetteville 7: 849, 1986) and K+ uptake were consistent; 2) alpha 2-adrenergic agonists inhibited both VIP-stimulated cAMP production (J. T. Turner, C. Ray-Prenger, and D. B. Bylund, Mol. Pharmacol. 28: 422, 1985) and K+ uptake; and 3) forskolin, but not dideoxyforskolin, mimicked the effects of VIP on K+ uptake. Because amiloride blocked the VIP-stimulated active K+ component, the VIP effects on active K+ influx may be secondary to a Na(+)-H+ antiporter-mediated increase in cellular Na+ content. Additional experiments indicated that pretreatment of cells with a protein kinase C activator, previously shown to decrease basal Na(+)-K(+)-Cl- cotransport activity and the apparent number of cotransporters in HT-29 cells (C. C. Franklin, J. T. Turner, and H. D. Kim, J. Biol. Chem. 264: 6667, 1989), did not change the magnitude of response of the remaining cotransporters after adenylate cyclase activation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vasoactive intestinal peptide stimulates active K+ transport and Na(+)-K(+)-Cl- cotransport in HT-29 cells. 230 69

Isolated rat enterocytes exposed to the insecticide lindane (the gamma-isomer of hexachlorocyclohexane, HCCH) showed an important decrease in the efficiency of the neuropeptide vasoactive intestinal peptide (VIP) upon the stimulation of cyclic AMP accumulation. The effect of lindane was time- and dose-dependent, optimal conditions being reached after 5 min incubation of cells at 25 degrees C with 0.5 mM of this organochlorine compound. Lindane action exhibited an important degree of specificity since the isomer alpha-HCCH and endrin reproduced the same inhibitory pattern but beta-HCCH and dieldrin were inactive. The inhibition of VIP-induced cyclic AMP accumulation could not be explained by a lindane-dependent reduction in the binding of VIP to its specific receptors. Among various possibilities, the results suggest the modification of membrane fluidity by lindane and/or the activation of Ca2+-dependent protein kinase C by this compound leading to phosphorylation of Gs/adenylate cyclase.
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PMID:Lindane effect upon the vasoactive intestinal peptide receptor/effector system in rat enterocytes. 246 74

Proteins in lacrimal gland fluid are secreted primarily by the acinar cells. Secretory proteins are synthesized in the endoplasmic reticulum, modified in the Golgi apparatus, stored in secretory granules, and released upon a change in the cellular level of second messenger. The second messenger level is controlled by a process termed signal transduction. Agonists, primarily neurotransmitters in the lacrimal gland, bind to receptors in the basolateral membrane of secretory cells. This interaction activates enzymes in the membrane that cause production of second messengers. It has been hypothesized that second messengers stimulate secretion by activating specific protein kinases to phosphorylate proteins important for secretion. In the lacrimal gland, cholinergic agonists stimulate protein secretion. They act by activating phospholipase C to break down phosphatidylinositol bisphosphate into 1,4,5-inositol trisphosphate (1,4,5-IP3) and diacylglycerol (DAG). 1,4,5-IP3 causes release of Ca2+ from intracellular stores. This Ca2+, perhaps in conjunction with calmodulin, activates specific protein kinases that may be involved in secretion. DAG activates protein kinase C which stimulates protein secretion. alpha 1-Adrenergic agonists also stimulate lacrimal gland protein secretion. These agonists use a pathway that is separate from that utilized by cholinergic agonists and vasoactive intestinal peptide (VIP). The specific pathway has not been identified but may be DAG and protein kinase C. VIP, beta-adrenergic agonists, alpha-melanocyte stimulating hormone, and adrenocorticotropic hormone are lacrimal gland secretagogues. They activate adenylate cyclase to produce cAMP. cAMP stimulates protein kinase A, which perhaps causes protein secretion. Thus, three separate cellular pathways stimulate lacrimal gland protein secretion. Cholinergic agonists and VIP also stimulate lacrimal gland fluid secretion, and the same signal transduction pathways utilized by these agonists to stimulate protein secretion are most likely used for electrolyte and water secretion.
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PMID:Signal transduction and control of lacrimal gland protein secretion: a review. 254 11

Pretreatment of rat prostatic epithelial cells with the tumor-promoting phorbol ester 4 beta-phorbol 12-myristate 13-acetate resulted in a decrease of both the potency of vasoactive intestinal peptide (VIP) upon the stimulation of cyclic AMP accumulation and the affinity of the receptors of this peptide. These effects were dose-dependent and could be reproduced by other stimulators of protein kinase C (PKC). Thus, it is conceivably that phosphorylation of VIP receptors by PKC regulates VIP receptor function in the prostate gland.
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PMID:Tumor-promoting phorbol esters interfere with the vasoactive intestinal peptide receptor/effector system in rat prostatic epithelial cells. 282 98

The purpose of this study was to determine whether vasoactive intestinal peptide (VIP) might have a presynaptic modulatory effect at cholinergic terminals in the rat hippocampal formation. The exposure of rat hippocampal slices to VIP increased [3H]acetylcholine ([3H]ACh) synthesis from the precursor [3H]choline when tissue was incubated in normal or in high K+ medium; the maximal effect was apparent at 10(-8) M VIP and 10(-7) M VIP, respectively. Also, 10(-7) M VIP increased the activity of choline acetyltransferase (ChAT) in a hippocampal homogenate system. The increased synthesis by hippocampal slices was not the result of a VIP-induced alteration in either the basal release of ACh or the uptake of choline via the high-affinity uptake system. The increase in ACh synthesis induced by VIP in hippocampal slices was not associated with either adenylate cyclase or protein kinase C second messenger systems. There was no correlation between the effect of VIP on cyclic AMP production with that on ACh synthesis; also, forskolin, an activator of adenylate cyclase that increased cyclic AMP production 3.5-fold, did not mimic the effect of VIP on ACh synthesis. Similarly, there was no effect of the protein kinase C activator, phorbol myristate acetate, on ACh synthesis in hippocampal slices. However, the effect of VIP to increase ACh synthesis was not evident in the absence of extracellular calcium, suggesting that the effect of VIP is mediated by a calcium-requiring mechanism. The results suggest that, in the rat hippocampus, VIP has a presynaptic action at cholinergic terminals that results in enhanced synthesis of ACh, possibly by an action that alters ChAT activity.
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PMID:Vasoactive intestinal peptide increases acetylcholine synthesis by rat hippocampal slices. 282 90

Phorbol esters alter cyclic AMP levels in a number of tissues, including the anterior pituitary. We report that membrane preparations from GH3 cells exposed to phorbol esters exhibit decreased vasoactive intestinal peptide (VIP)-stimulated and enhanced forskolin-stimulated adenylate cyclase activity. The responsiveness of adenylate cyclase activity to NaF, guanylyl-imidodiphosphate, and Mn2+ was also reduced by phorbol ester treatment. The ability of somatostatin to inhibit forskolin-stimulated adenylate cyclase activity was reduced while phorbol ester exposure had no apparent effect on somatostatin inhibition of VIP-stimulated adenylate cyclase activity. We suggest that protein kinase C alters at least two distinct components of the adenylate cyclase system. One modification disrupts hormone receptor-Gs interaction (lowering VIP efficacy) and the second perturbation augments the activity of the adenylate cyclase catalytic subunit.
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PMID:Phorbol esters induce two distinct changes in GH3 pituitary cell adenylate cyclase activity. 283 67

The effects of the active phorbol ester 12-myristate, 13-acetate (PMA), the inactive ester 4 alpha-phorbol 12,13-didecanoate (4 alpha-PDD), and the synthetic diacylglycerol 1-oleoyl-2-acetyl-glycerol (OAG) on cyclic AMP production were examined in rat cerebral cortical and diencephalic cells. With the aid of a prelabeling technique for measuring cyclic AMP accumulation in the cells, it was found that neither PMA nor OAG significantly increased cyclic AMP formation in either type of cell. In contrast, PMA enhanced the cyclic AMP response to vasoactive intestinal peptide (VIP) and forskolin in cerebral cortical and diencephalic cells, whereas 4 alpha-PDD was inactive. A 15-min preincubation was used to obtain maximal enhancement. The concentration dependence of PMA on VIP-stimulated cyclic AMP accumulation was determined in cortical cells (EC50 = 6.2 x 10(-8) M). OAG was also able to potentiate VIP-induced cyclic AMP formation in cortical and diencephalic cells. However, its potentiating effect was weaker than that observed with PMA treatment. The data show, at an early stage of development (primary cultures, 8-10 days), a modulation of VIP- or forskolin-cyclic AMP response by the activators of protein kinase C, i.e., PMA and OAG, in two different structures of the central nervous system: the cerebral cortex and the diencephalon. To our knowledge, this is the first demonstration of such a potentiation within the diencephalon.
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PMID:Activators of protein kinase C enhance cyclic AMP accumulation in cerebral cortical and diencephalic neurons in primary culture. 284 13

The augmentation of isoproterenol or vasoactive intestinal peptide (VIP)-stimulated cyclic AMP accumulation in rat brain slices by the GABAB agonist baclofen was compared to that mediated by tumor-promoting phorbol esters. The protein kinase C inhibitor H7 and desensitization of protein kinase C reduced the cyclic AMP augmenting effect of the phorbol ester, but not baclofen. Incubation of brain slices in the presence of both baclofen and a phorbol ester amplified the cyclic AMP response to isoproterenol or VIP to a greater degree than that found with either baclofen or the phorbol ester alone, with the increased augmentation appearing to be additive. These findings indicate that although stimulation of GABAB receptors or protein kinase C activation by phorbol esters have similar effects on transmitter-stimulated cyclic AMP production in brain, these augmenting actions appear to be independently mediated.
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PMID:Augmentation of neurotransmitter receptor-stimulated cyclic AMP accumulation in rat brain: differentiation between the effects of baclofen and phorbol esters. 285 13

Hormonal activation and inhibition of the GH4Cl1 cell adenylate cyclase complex is delineated. In the presence of the guanyl nucleotide GTP, enzyme activity was enhanced twofold by thyroliberin, sixfold by vasoactive intestinal peptide (VIP), twofold by prostaglandin E2 and twofold by isoproterenol. The diterpene, forskolin, increased, the activity 14-fold. In the presence of high GTP (400 microM) and NaCl (150 mM) concentrations, somatostatin inhibited (ED50 = 0.5 microM) the cyclase activity by 40%. In the presence of 10 microM somatostatin, the ED50 values (5 nM) for thyroliberin- and VIP-stimulated adenylate cyclase activities were shifted to 20 nM. Forskolin-elicited activation was, however, not affected by somatostatin. Cholera-toxin and pertussis-toxin pretreatment of the enzyme brought about some 20-fold and twofold activation, respectively. Inhibition by somatostatin was abolished upon pre-exposure to pertussis toxin. Mild alkylation by N-ethylmaleimide increased basal and hormone-activated adenylate cyclase while somatostatin again failed to express its inhibitory potential. Further alkylation caused a gradual decline and convergence of hormone-modulated cyclase activities towards zero. The N-ethylmaleimide-induced attenuation of thyroliberin-elicited activity was paralleled by a decrease in [3H]thyroliberin binding. Trifluoperazine and an anti-calmodulin serum reduced basal and net thyroliberin-, VIP- and forskolin-enhanced cyclase activities by some 30%, 100%, 70% and 80%, respectively. The Vmax of basal and thyroliberin-stimulated adenylate cyclase was diminished by 65%, leaving the apparent Km values (7.2 mM and 2.6 mM, respectively) for Mg2+ unaltered. Finally, the phorbol ester 12-O-tetra-decanoyl-phorbol 13-acetate (TPA) doubled the activity. This effect was counteracted by the protein kinase C inhibitor, polymyxin B, while thyroliberin-enhanced adenylate cyclase remained unaffected. In summary, we have described an adenylate cyclase with stimulatory (Rs) and inhibitory (Ri) receptors coupled to a calmodulin-sensitive holoenzyme through the Gs and Gi type of GTP-binding proteins. The ratio of the Gs to Gi is high. It appears that the GH4C1 cell adenylate cyclase is also activated by protein kinase C by interference with Gi. Apparently, thyroliberin activates the cyclase both directly through Gs and indirectly via protein kinase C stimulation.
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PMID:Hormone-sensitive adenylate cyclase of prolactin-producing rat pituitary adenoma (GH4C1) cells: molecular organization. 290 68


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