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 current studies have implicated a prominent role for PACAP peptides in modulating the physiological function of cells derived from the sympathoadrenal lineage. Compared to VIP, both PACAP-27 and PACAP-38 demonstrated potent, efficacious, and sustained stimulatory effects on sympathetic neuronal NPY and catecholamine production. The differential effects of PACAP peptides on SCG NPY and catecholamine content and secretion coincided with previous studies that activated directly the sympathetic intracellular cyclic AMP-protein kinase A signaling pathway. These effects appear to be mediated primarily by PACAP1 receptor splice variants coupled to both adenylyl cyclase and phospholipase C in SCG neurons. The actions of PACAP peptides in the SCG shared many parallels with adrenal medullary chromaffin cells, suggesting diverse roles for the PACAP peptidergic system in sympathoadrenal cell development and function. Rather than solutions, these results pose additional questions for the future. What are the endogenous sources of PACAP that regulate sympathetic and adrenal function? Do PACAP peptides, like VIP, have dual roles and also act as sympathetic postganglionic neuromodulators? Are VIP/PACAP receptors expressed during SCG development? What regulates sympathetic PACAP1 receptor isoform expression and how are they differentially coupled to neuronal intracellular signaling cascades? What defines the tissue-specific responses to PACAP-27 and PACAP-38? While many of these questions are not easily approached, future studies of these issues will certainly illuminate the function of PACAP and PACAP receptors in the nervous and endocrine systems.
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PMID:Pituitary adenylate cyclase-activating polypeptides, PACAP-38 and PACAP-27, regulation of sympathetic neuron catecholamine, and neuropeptide Y expression through activation of type I PACAP/VIP receptor isoforms. 899 4

Signal transduction in gastric and intestinal smooth muscle is mediated by receptors coupled via distinct G proteins to various effector enzymes, including PI-specific PLC-beta 1 and PLC-beta 3, and phosphatidylcholine (PC)-specific PLC, PLD and PLA2. Activation of these enzymes is different in circular and longitudinal muscle cells, generating Ca(2+)-mobilizing (IP3, AA, cADPR) and other (DAG) messengers responsible for the initial and sustained phases of contraction, respectively. IP3-dependent Ca2+ release occurs only in circular muscle. Ca2+ mobilization in longitudinal muscle involves a cascade initiated by agonist-induced transient activation of PLA2 and formation of AA, AA-dependent depolarization of the plasma membrane and opening of voltage-sensitive Ca2+ channels. The influx of Ca2+ induces Ca2+ release by activating sarcoplasmic ryanodine receptor/Ca2+ channel and stimulates cADPR formation which enhances Ca(2+)-induced Ca2+ release. The initial [Ca2+]i transient in both muscle cell types results in Ca2+/calmodulin-dependent activation of MLC kinase, phosphorylation of MLC20 and interaction of actin and myosin. The sustained phase is mediated by a Ca(2+)-independent isoform of PKC, PKC-epsilon DAG for this process is generated by PLC- and PLD-mediated hydrolysis of PC. Relaxation is mediated by cAMP-and/or cGMP-dependent protein kinase which inhibit the initial [Ca2+]i transient and reduce the sensitivity of MLC kinase to [Ca2+]i. Relaxation induced by the main neurotransmitters, VIP and PACAP, involves two cascades, one of which reflects activation of adenylyl cyclase. A distinct cascade involves G-protein-dependent stimulation of Ca2+ influx leading to Ca2+/calmodulin-dependent activation of a constitutive eNOS in muscle cells; the generation of NO activates soluble guanylyl cyclase. The resultant activation of PKA and PKG is jointly responsible for muscle relaxation.
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PMID:Signal transduction in gastrointestinal smooth muscle. 921 27

The ability of cAMP-dependent protein kinase (PKA) to phosphorylate type I, II, and III inositol 1,4,5-trisphosphate (InsP3) receptors was examined. The receptors either were immunopurified from cell lines and then phosphorylated with purified PKA or were phosphorylated in intact cells after activating intracellular cAMP formation. The former studies showed that the type I receptor was a good substrate for PKA (0.65 mol Pi incorporated/mol receptor), whereas type II and III receptors were phosphorylated relatively weakly. The latter studies showed that despite these differences, each of the receptors was phosphorylated in intact cells in response to forskolin or activation of neurohormone receptors. Detailed examination of SH-SY5Y neuroblastoma cells, which express >/=99% type I receptor, revealed that minor increases in cAMP concentration were sufficient to cause maximal phosphorylation. Thus, VIP and pituitary adenylyl cyclase activating peptide (acting through Gs-coupled pituitary adenylyl cyclase activating peptide-I receptors) were potent stimuli of type I receptor phosphorylation, and remarkably, even slight increases in cAMP concentration induced by carbachol (acting through Gq-coupled muscarinic receptors) or other Ca2+ mobilizing agents were sufficient to cause phosphorylation. Finally, PKA enhanced InsP3-induced Ca2+ mobilization in a range of permeabilized cell types, irrespective of whether the type I, II, or III receptor was predominant. In summary, these data show that all InsP3 receptors are phosphorylated by PKA, albeit with marked differences in stoichiometry. The ability of both Gs- and Gq-coupled cell surface receptors to effect InsP3 receptor phosphorylation by PKA suggests that this process is widespread in mammalian cells and provides multiple routes by which the cAMP signaling pathway can influence Ca2+ mobilization.
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PMID:Phosphorylation of inositol 1,4,5-trisphosphate receptors by cAMP-dependent protein kinase. Type I, II, and III receptors are differentially susceptible to phosphorylation and are phosphorylated in intact cells. 948 97

We showed previously that pituitary adenylate cyclase-activating polypeptide (PACAP) increases glycoprotein hormone alpha-subunit gene expression and secretion in alphaT3-1 cells. We have now used 5'-flanking deletion and clustered point mutations of the mouse alpha-subunit promoter fused to the luciferase (LUC) reporter gene in transient transfection assays to further characterize the cell signaling pathways and sequences involved in responsiveness to PACAP. PACAP stimulated LUC activity at a lower concentration than VIP, supporting the notion that PACAP acts through type 1 receptors. The effect of PACAP on LUC activity was observed by 2 h, peaked at 4-12 h, and persisted until at least 20 h. alphaT3-1 cells were transfected with mouse alpha-LUC constructs truncated at -507, -424, -288, -205, -146, and -133, and treated with PACAP, a cell-permeable cAMP analog (8Br-cAMP), phorbol myristate acetate (PMA), or control medium. Transcriptional activation by PACAP was highest with the -288 and -205 mouse alpha-LUC vectors (7-8-fold stimulation) and decreased significantly with truncation of the 5'-flanking region to -146 or -133. The pattern of alpha-subunit stimulation by cAMP closely paralleled that of PACAP. With PMA, stepwise decrements in LUC activity were observed between -507 and -424 and, especially, -424 and -288, and there was no further loss of activity with deletion to -205, -146, or -133. Clustered point mutations in the pituitary glycoprotein hormone basal element (-337 to -330) or the gonadotropin-releasing hormone response element (GnRH-RE)(-406 to -399) of the -507 to +46 mouse alpha-promoter significantly (P < 0.05) increased and decreased, respectively, PACAP's effect on transcriptional activity. These results indicate that there are several regions of the mouse alpha-subunit promoter that mediate responsiveness to PACAP. The co-localization of PACAP and cAMP responsiveness as well as the results of studies involving specific inhibitors of protein kinase A (H-89) or protein kinase C (PKC) (bisindolylmaleimide) suggests that the action of PACAP on alpha-subunit transcription is mediated primarily by the protein kinase A (PKA) pathway.
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PMID:Transcriptional regulation of the glycoprotein hormone alpha-subunit gene by pituitary adenylate cyclase-activating polypeptide (PACAP) in alphaT3-1 cells. 960 11

Phosphorylation of the transcription factor CREB appears as an important step in the signal transduction cascade that activates melatonin biosynthesis in the mammalian pineal organ. We have studied the mechanisms causing CREB phosphorylation by immunocytochemical and immunochemical demonstration of phosphorylated CREB (pCREB) in isolated, immunocytochemically identified rat pinealocytes kept in vitro and in the rat pineal organ in situ. Norepinephrine (NE), the most potent stimulator of the melatonin biosynthesis was shown to induce pCREB immunoreaction (i.r.) in the vast majority of pinealocytes in a time- and dose-dependent manner. This response was elicited by stimulation of beta-adrenergic receptors resulting in an increase in the intracellular cAMP concentration. Activation of alpha 1-adrenergic receptors that causes a rise in intracellular calcium via stimulation of intracellular stores and subsequent increase in calcium influx did not evoke pCREB ir on its own and did not potentiate the beta-adrenergic response. VIP and PACAP that activate the melatonin biosynthesis to a lesser extent than NE induced pCREB ir in only 50-60% of the pinealocytes. Immunoblotting showed that a protein of 43 kDa corresponding to CREB accounts for the pCREB ir and confirmed that VIP and PACAP are less effective in inducing CREB phosphorylation than NE. The amount of total (phosphorylated and unphosphorylated) CREB was not changed upon stimulation of the cells with NE, VIP or PACAP. In an attempt to identify the protein kinase catalyzing CREB phosphorylation in rat pinealocytes, the cAMP-dependent protein kinases (cAK) present in the rat pineal were identified with the use of antibodies recognizing different catalytic and regulatory subunits. Application of cAK agonists and antagonists showed that the cAK type II is responsible for CREB phosphorylation. Correlations between the melatonin concentration in the medium and the CREB phosphorylation in pinealocytes revealed a tight connection between these two parameters. Phosphorylation of CREB appears important for the stimulation of melatonin biosynthesis also under natural conditions because our investigations of whole pineal organs taken from rats during different time points of the 24 h light-dark cycle revealed a strong induction of pCREB ir in the first part of the night.
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PMID:Control of CREB phosphorylation and its role for induction of melatonin synthesis in rat pinealocytes. 961

Astrocytes, a subtype of glial cells, have been demonstrated to have an abundant number of receptors for pituitary adenylate cyclase activating polypeptide (PACAP), a neuropeptide of the VIP/secretin family which stimulates cAMP accumulation 1000 times more potent than VIP in astrocytes. PACAP is reported to stimulate the proliferation of astrocytes at low concentrations at which it does not yet stimulate the cAMP accumulation. In the present study, we examined the effect of PACAP on the activation of mitogen-activated protein kinase (MAPK), one of the important intracellular signals for the proliferation, and compared it with that of epidermal growth factor (EGF). To investigate the activation of MAPK, we focused on ERK2, one of MAPK, in cultured rat astrocytes. The activation of ERK2 was determined by immunoblotting and measurement of the activity in terms of the phosphorylating activity of immunoprecipitates with MAPK antibody on myelin basic protein. One pM of PACAP38 temporarily activated ERK2 at 10 min. In contrast, EGF activated ERK2 from 10 min to 60 min continuously. As for the dose-response effect, PACAP stimulated ERK2 at as low a concentration as 10-14 M and peaked at 10-12 M. Thereafter, its activating effect gradually decreased at 10-10 M and returned to the basal level at 10-8 M, forming a bell-shaped dose-dependency. Neither an inhibitor of PKA (H89) nor inhibitors of PKC (staurosporine and calphostin C) had any effect on the ERK2 activation induced by 1 pM PACAP38. Dibutyryl cAMP suppressed ERK2 activity in a dose-dependent manner. These data clearly demonstrated that PACAP stimulates MAPK in both a PKA- and a PKC-independent manner in cultured rat astrocytes.
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PMID:Pituitary adenylate cyclase activating polypeptide (PACAP) stimulates mitogen-activated protein kinase (MAPK) in cultured rat astrocytes. 962 27

Pituitary adenylate cyclase activating polypeptide (PACAP) was shown to relax guinea pig gallbladder strips contracted with cholecystokinin. This relaxation was mediated by PACAP interacting with VIP/PACAP receptors. PACAP was also shown to cause contraction in guinea pig gallbladder strips. The present study demonstrated that calphostin C and bisindolylmaleimide IV, both blockers of protein kinase C, significantly reduced tension, Rp-adenosine 3', 5'-cyclic monophosphatase triethylamine, a blocker of protein kinase A, had no effect on PACAP-induced tension. Nifedipine also significantly reduced the PACAP effect. The contractile effects of PACAP are mediated by protein kinase C.
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PMID:Protein kinase C mediates the contractile actions of pituitary adenylate cyclase activating polypeptide in guinea pig gallbladder strips. 980 97

A cellular suspension from rat submandibular glands was prepared with collagenase. The intracellular pH (pHi) was estimated with 2',7'-bis-(2-carboxy-ethyl)-5(6)-carboxyfluorescein (BCECF). After exposure to NH4Cl, the pHi transiently increased (diffusion of NH3) and then dropped (influx of NH4+). Isoproterenol increased 2.5-fold the rate of NH4+ influx; bumetanide, an inhibitor of the Na+-K+-2Cl(-)-cotransporter blocked the response to isoproterenol, confirming that the beta-adrenergic agonist stimulated the cotransporter. Forskolin (1 micromol/L) mimicked the response to isoproterenol. VIP (1 nmol/L(-1) micromol/L) also increased the activity of the cotransporter. Cyclic AMP rather than calcium was the mediator of this activation since 1) carbachol which increased the [Ca2+]i fivefold increased the uptake of NH4+ by only 50%; 2) only high concentrations of VIP significantly increased the [Ca2+]i; 3) incubation in the presence of EGTA had no effect on the response to VIP; 4) low concentrations (nmol/L) of the neuropeptide increased the intracellular level of cAMP; and 5) the stimulation of the cotransporter by VIP, forskolin, and isoproterenol was inhibited by H8, an inhibitor of cAMP-dependent protein kinase. It is concluded that the Na+-K+-2Cl(-)-cotransporter of rat submandibular glands is activated by isoproterenol, forskolin, and neuropeptides of the VIP family by a mechanism involving cAMP-dependent processes. The activation of the cotransporter by VIP could partly explain the potentiating effect of VIP on the response to sialagogues like substance P or muscarinic agonists.
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PMID:Activation of the Na+-K+(NH4+)-2Cl(-)- cotransporter from rat submandibular glands in response to VIP. 988 83

The cis-acting elements of the VIP gene important for basal and stimulated transcription have been studied by transfection of VIP-reporter gene constructs into distinct human neuroblastoma cell lines in which VIP transcription is constitutively high, or can be induced to high levels by protein kinase stimulation. The 5.2 kb flanking sequence of the VIP gene conferring correct basal and inducible VIP gene expression onto a reporter gene in these cell lines was systematically deleted to define its minimal components. A 425-bp fragment (-4656 to -4231) fused to the proximal 1.55 kb of the VIP promoter-enhancer was absolutely required for cell-specific basal and inducible transcription. Four additional components of the VIP gene were required for full cell-specific expression driven by the 425 bp TSE (region A). Sequences from -1.55 to -1.37 (region B), -1.37 to -1.28 (region C), -1.28 to -.094 (region D), and the CRE-containing proximal 94 bp (region E) were deleted in various combinations to demonstrate the specific contributions of each region to correct basal and inducible VIP gene expression. Deletion of region B, or mutational inactivation of the CRE in region E, resulted in constructs with low transcriptional activity in VIP-expressing cell lines. Deletion of regions B and C together resulted in a gain of transcriptional activity, but without cell specificity. All five domains of the VIP gene were also required for cell-specific induction of VIP gene expression with phorbol ester. Gelshift analysis of putative regulatory sequences in regions A-D suggests that both ubiquitous and neuron-specific trans-acting proteins participate in VIP gene regulation.
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PMID:Cis-regulatory elements controlling basal and inducible VIP gene transcription. 992 92

Gastric inhibitory polypeptide (GIP) is a 42-amino acid peptide, belonging to the VIP-secretin-glucagon superfamily, some members of this group are able to regulate adrenocortical function. GIP-receptor mRNA has been detected in the rat adrenal cortex, but investigations on the effect of GIP on steroid-hormone secretion in this species are lacking. Hence, we have investigated the distribution of GIP binding sites in the rat adrenal gland and the effect of their activation in vivo and in vitro. Autoradiography evidenced abundant [125I]GIP binding sites exclusively in the inner adrenocortical layers, and the computer-assisted densitometric analysis of autoradiograms demonstrated that binding was displaced by cold GIP, but not by either ACTH or the selective ACTH-receptor antagonist corticotropin-inhibiting peptide (CIP). The intraperitoneal (IP) injection of GIP dose-dependently raised corticosterone, but not aldosterone plasma concentration: the maximal effective dose (10 nmol/rat) elicited a twofold increase. GIP did not affect aldosterone and cyclic-AMP release by dispersed zona glomerulosa cells. In contrast, GIP enhanced basal corticosterone secretion and cyclic-AMP release by dispersed inner adrenocortical cells in a concentration-dependent manner, and the maximal effective concentration (10(-7) M) evoked 1.5- and 2.4-fold rises in corticosterone and cyclic-AMP production, respectively. GIP (10(-7) M) did not display any additive or potentiating effect on corticosterone and cyclic-AMP responses to submaximal or maximal effective concentrations of ACTH. The corticosterone secretagogue action of 10(-7) M GIP was abolished by the protein kinase A (PKA) inhibitor H-89 (10(-5)M), and unaffected by CIP (10(-6)M). Collectively, these findings indicate that GIP exerts a moderate but statistically significant stimulatory effect on basal glucocorticoid secretion in rats, acting through specific receptors coupled with the adenylate cyclase/PKA-dependent signaling pathway.
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PMID:Gastric inhibitory polypeptide stimulates glucocorticoid secretion in rats, acting through specific receptors coupled with the adenylate cyclase-dependent signaling pathway. 1046 10


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