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)

Posttranslational processing of the pro-growth hormone-releasing hormone (proGHRH) peptide can result in the formation of at least two peptide products: GHRH and the C-terminal peptide, GHRH-related peptide (GHRH-RP). While cyclic adenosine monophosphate transduces many of the actions of GHRH, other pathways also have been implicated in its actions. The aims of this study were to examine and characterize the activation of mitogen-activated protein kinase (MAPK) pathways by GHRH, and GHRH-RP in pituitary-derived GH3 cells, as well as the activation of the transcription factors that serve as substrates for these kinases. GHRH rapidly increased p44/p42 MAPK activity in GH3 cells in a protein kinase A-dependent and a protein kinase C-independent manner and stimulated the activation of the transcription factor Elk-1. By contrast, GHRH-RP and p75-92NH2 had no effect on p44/p42 MAPK phosphorylation in these cells. Additionally, we determined that all three peptides, GHRH, GHRH-RP, and p75-92NH2, rapidly and specifically increase phosphorylation of p38 MAPK and stimulate the activation of the nuclear factor CHOP. These are the first studies to demonstrate the activation of Elk-1 by GHRH and the activation of p38 MAPK and CHOP by GHRH, GHRH-RP, and p75-92NH2. We conclude that members of the GHRH family of peptides differentially activate multiple intracellular signaling pathways and suggest that the biologic actions of GHRH may be far more diverse than previously thought.
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PMID:Peptides derived from pro-growth hormone-releasing hormone activate p38 mitogen-activated protein kinase in GH3 pituitary cells. 1157 18

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a basic 38-amino acid peptide, which acts through three main G protein-coupled VIP/PACAP receptor subtypes, called PAC1, VPAC1 and VPAC2. We have investigated the expression and function of PACAP and its receptors in the rat adrenal gland. Reverse transcription (RT)-polymerase chain reaction (PCR) and radioimmune assay (RIA) allowed the detection of PACAP expression as mRNA and protein exclusively in adrenal medulla (AM). RT-PCR and quantitative autoradiography, using [(125)I]PACAP and selective VIP/PACAP receptor ligands, demonstrated the expression of PAC1 only in AM, and VPAC1 and VPAC2 in both AM and zona glomerulosa (ZG), PACAP receptor expression being absent in zona fasciculata/reticularis (ZF/R). PACAP38 concentration-dependently increased aldosterone secretion from dispersed ZG cells and catecholamine secretion from AM tissue, the maximal effective concentration being 10(-7) M. ZF/R cells did not display any secretory response to PACAP38. Aldosterone response of ZG cells to 10(-7) M PACAP38 was unaffected by the PAC1-antagonist (A) PACAP(6-38), and significantly decreased by the VPAC1-A [Ac-His(1),D-Phe(2),Lys(15),Arg(16)]VIP(3-7) GRF(8-27)-NH(2). Catecholamine response of AM tissue to PACAP38 was reduced, but not abolished, by both PAC1-A and VPAC1-A. The VPAC2 agonist (ago) Ro25-1553 elicited sizeable secretory responses from both ZG cells and AM tissue. PACAP38 (10(-7) M) evoked a marked rise in cyclic-AMP (cAMP) and inositol-1,4,5-triphosphate (IP3) production by ZG cells and AM tissue. cAMP response of ZG cells was lowered by VPAC1-A, and that of AM tissue by both PAC1-A and VPAC1-A. IP3 response of ZG cells and AM tissue was unaffected by PAC1-A and decreased by VPAC1-A. VPAC2-ago did not affect cAMP release, but raised IP3 production by both ZG cells and AM tissue. Aldosterone response of ZG cells and catecholamine response of AM tissue to PACAP38 (10(-7) M) were reduced by the adenylate cyclase (AC) and phospholipase-C (PLC) inhibitors (I) SQ-22536 and U-73122, as well as by the protein kinase (PK)A-I H-89 and PKC-I calphostin-C. Conversely, the secretory responses of both ZG and AM preparations to VPAC2-ago were annulled by PLC-I, lowered by PKC-I, and unaffected by either AC-I or PKA-I. Collectively, our findings allow us to conclude that in the rat adrenals: i) PACAP biosynthesis exclusively occurs in the AM; ii) ZG cells are provided with functional VPAC1 and VPAC2 receptors, whose activation by PACAP evokes a moderate aldosterone response; iii) AM cells possess all the subtypes of VIP/PACAP receptors, whose activation by PACAP elicits a marked catecholamine response; and iv) PAC1 receptors are coupled to the AC-dependent cascade, VPAC1 receptors to both the AC- and PLC-dependent cascades, and VPAC2 receptors exclusively to the PLC-dependent cascade.
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PMID:Pituitary adenylate cyclase-activating polypeptide and PACAP receptor expression and function in the rat adrenal gland. 1183 29

Ras activation induces a variety of cellular responses that depend on the specific activated effector, the intensity and amplitude of its activation, and the cellular type. Transient activation followed by a sustained but low signal of the Ras/Raf/MEK/ERK pathway is a common feature of cell proliferation in many systems. On the contrary, sustained, high activation is linked with either senescence or apoptosis in fibroblasts and to differentiation in neurones and PC12 cells. The temporal regulation of the pathway is relevant and not only depends on the specific receptor activated but also on the presence of diverse modulators of the pathway. We review here evidence showing that calcium (Ca(2+)) and calmodulin (CaM) are able to regulate the Ras/Raf/MEK/ERK pathway. CaM-binding proteins (CaMBPs) as Ras-GRF and CaM-dependent protein kinase IV (CaMKIV) positively modulate ERK1/2 activation induced by either NGF or membrane depolarisation in neurones. In fibroblasts, CaM binding to EGF receptor and K-Ras(B) may be involved in the downregulation of the pathway after its activation, allowing a proliferative signalling.
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PMID:Modulation of the Ras/Raf/MEK/ERK pathway by Ca(2+), and calmodulin. 1202 Jul 64

Long-term in vivo treatment with synthetic GH-releasing peptides (GHRPs) enhances the release of GH induced by endogenous GHRH. The mechanism for such an enhancement on GH release is unknown. In this experiment, somatotropes were obtained from ovine pituitaries by enzyme dissociation and enriched by density centrifugation. Membrane voltage and currents were recorded with whole-cell patch-clamp configuration. After 48-h treatment with GHRP-2 (10(-8) M), the percentage of cells with spontaneous action potential was increased (51 vs. 27%) without change of resting potential. This GHRP-2 treatment also increased the amplitude of voltage-gated K+ currents (predominantly transient A-type-like current but also delayed rectifier or K-type-like current) without modification of biophysical kinetics. Down-regulation of protein kinase C (PKC) with phorbol 12-myristate 13-acetate at the time of adding GHRP-2 blocked the increase in K+ currents. Inclusion of calphostin C (PKC inhibitor) but not H(89) (protein kinase A inhibitor) significantly reduced the increase in K+ currents by GHRP-2. Inclusion of actinomycin D (transcription inhibitor) or cycloheximide (protein synthesis inhibitor) abolished the increase in K+ currents. These data indicate that 48-h GHRP-2 treatment increases the density of K+ channels via PKC and channel protein synthesis. Such a modification on K+ channels by GHRP-2 may be partially responsible for the change of somatotrope electrophysiological properties and sensitivity to GHRH stimulation.
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PMID:The effect of two-day treatment of primary cultured ovine somatotropes with GHRP-2 on membrane voltage-gated K+ currents. 1207 99

VIP and PACAP38 are closely related peptides that are released in the adrenal gland and sympathetic ganglia and regulate catecholamine synthesis and release. We used PC12 cells as a model system to examine receptor and second messenger pathways by which each peptide stimulates transcriptional and post-transcriptional mechanisms that regulate the level of the mRNA for tyrosine hydroxylase (TH), the rate-limiting enzymatic step in catecholamine synthesis. Concentration-response studies revealed that PACAP38 had both greater efficacy and potency than VIP. The specific PAC1 receptor antagonist PACAP[6-38] blocked the effects of each peptide on TH mRNA content while the PACAP/VIP type II receptor antagonist (N-AC-Tyr(1)-D-Phe(2))-GRF-(1-29)-NH(2) was without effect. At equipotent concentrations, each peptide stimulated a transient increase in TH gene transcription lasting less than 3h. Continuous VIP treatment stimulated a transient increase in TH mRNA lasting less than 24h. In contrast, continuous exposure to PACAP38 stimulated a stable increase in TH mRNA that persisted for 2 days in the absence of elevated transcription, pointing to different post-transcriptional effects of the two peptides. PACAP38 alone had no effect on the magnitude of TH gene transcription or TH mRNA in A126-1B2 PKA-deficient PC12 cells. However, when combined with dexamethasone, PACAP38 produced a synergistic increase in TH mRNA in the absence of PACAP38-stimulated TH gene transcription. In contrast, VIP had no effect on either TH mRNA content or TH gene transcription in this model. PACAP38, but not VIP, stimulated PKC activity. Calphostin C antagonized the effect of PACAP38 on the persistent post-transcriptional elevation in TH mRNA. Thus, the results support the conclusion that VIP and PACAP38 each stimulate PAC1 receptors to increase TH gene transcription through a PKA-controlled pathway, but their divergent post-transcriptional effects result at least partly from differing abilities to stimulate PKC.
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PMID:Transcriptional and post-transcriptional regulation of tyrosine hydroxylase messenger RNA in PC12 cells during persistent stimulation by VIP and PACAP38: differential regulation by protein kinase A and protein kinase C-dependent pathways. 1214 12

Orexins are recently discovered neuropeptides that play an important role in the regulation of hormone secretion, and their receptors have been recently demonstrated in the pituitary. The effects of orexin-A on voltage-gated Ca2+ currents and GH release in primary cultured ovine somatotropes were examined. The expression of orexin-1 receptor was demonstrated by RT-PCR in ovine somatotropes, from which Ca2+ currents were also isolated as L, T, and N currents. Application of orexin-A (100 nM) significantly and reversibly increased only the L current, and coadministration of orexin-A and GHRH (10 nM) showed an additive effect on this current, but no effect of orexin-A was observed on either T or N current. Furthermore, the orexin-A-induced increase in the L current was completely abolished by the inhibition of protein kinase C (PKC) activity using calphostin C (100 nM), phorbal 12,13-dibutyrate pretreatment (0.5 micro M) for 16 h or specific PKC inhibitory peptide PKC(19-36) (1 mM). However, the increase in L current by orexin-A was sustained when cells were preincubated with a specific protein kinase A blocker H89 (1 micro M) or a specific intracellular Ca2+ store depleting reagent thapsigargin (1 micro M). Finally, orexin-A alone did not significantly increase GH release, but coadministration of orexin-A and GHRH showed a synergistic effect on GH secretion in vitro. Our results therefore suggest that orexin-A may play an important role in regulating GHRH-stimulated GH secretion through the enhancement of the L-type Ca2+ current and the PKC-mediated signaling pathway in ovine somatotropes.
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PMID:Orexin-A augments voltage-gated Ca2+ currents and synergistically increases growth hormone (GH) secretion with GH-releasing hormone in primary cultured ovine somatotropes. 1244 88

The G protein-coupled receptor (GPCR) activation has been demonstrated to affect the ERK1/2 cascade in different cell lines. We investigated the effects of hypothalamic neuropeptides acting via GPCR on this pathway in GH-secreting (GH-oma) and nonsecreting (NFPA) pituitary adenomas. GHRH increased ERK1/2 activity (236 +/- 80%) in both gsp- and gsp+ GH-omas, this effect being almost completely abolished by protein kinase C (PKC) blockade. Both GnRH and pituitary adenylate-activating peptide caused a similar PKC-dependent activation of ERK1/2 in most NFPA. Increasing cAMP by forskolin caused a protein kinase A-dependent increase of ERK activity (287 +/- 37%) in GH-omas and had no effect in NFPA. ERK cascade blockade in GH-omas did not affect basal and GHRH-stimulated GH release, whereas it totally prevented the 3-fold increase in cyclin D1 protein expression induced by GHRH. In conclusion, this study demonstrated that in pituitary adenomas the activation of GPCR by neurohormones caused a PKC-dependent activation of ERK1/2 cascade that, at least in GH-omas, resulted to be involved in cyclin D1 induction by GHRH. Moreover, a stimulatory effect of the protein kinase A-dependent pathway on ERK1/2 cascade occurred selectively in GH-omas, probably contributing to the mitogenic potential of the cAMP pathway in this cell type.
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PMID:Effects of hypothalamic neuropeptides on extracellular signal-regulated kinase (ERK1 and ERK2) cascade in human tumoral pituitary cells. 1267 59

In recent years, one of the most exciting advances in the researches of pituitary adenomas is the discovery that 30%-40% of human pituitary somatotrophinomas carry somatic mutations of the gene for the alpha-subunit of the stimulatory GTP-binding protein, Gs (Gs alpha). These mutations, termed gsp oncogenes, may play an important role in the tumorigenesis of pituitary adenomas. Of 10 somatotrophinomas examined, 3 (30%) were proved to be gsp positive, as determined by sequence analysis of DNA generated by the polymerase chain reaction (PCR). GHRH exerted a significant stimulatory effect on GH secretion in 2 of 3 gsp-positive and 4 of 7 gsp-negative tumors. Moreover, phorbol ester, 1, 2-tetradecanoylphorbol-13-acetate (TPA), enhanced stimulation of lated the GH secretion effect exerted by GHRH in gsp-positive somatotrophinomas, whereas this effect was not observed in gsp-negative tumors. This result suggests that the protein kinase C signal system as well as adenylyl cyclase-cAMP-protein kinase A intracellular signal transduction system plays a pivotal role in GH secretory control of GHRH, which may work together via a cross-talk mechanism.
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PMID:TPA enhances growth hormone (GH) secretion effect of GH-releasing hormone (GHRH) by human gsp-positive pituitary somatotrophinomas. 1284 Sep 4

The effects of the novel GH-releasing hexapeptide, Hexarelin, on the secretion of GH in cultured human pituitary somatotrophinomas was further investigated. Hexarelin (20 nmol/L) strongly stimulated GH secretion, which could be reduced by phloretin, but not by RP-cAMPS, an inhibitor of protein kinase A (PKA). (Ac-Tyr1,D-Arg2)-GRF(1-29)-NH2 failed to block the effects of Hexarelin but completely abolished the stimulation of GH secretion exerted by GHRH. When added alone to somatotrophinoma cell cultures, Hexarelin had no effect on cAMP levels, but it potentiated the stimulatory effects of GHRH. These results demonstrated that Hexarelin could directly stimulate GH secretion by human pituitary somatotrophs PKC-dependently, which might be contributed to the activation of the PI transduction system. In addition, Hexarelin could interact with GHRH on the adenylyl cyclase system.
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PMID:Interaction of the novel GH secretagogue hexarelin with GHRH in regulating the secretion of GH by cultured human pituitary somatotrophinomas in vitro. 1284 19

Increasing evidence suggests that pituitary adenylate cyclase-activating polypeptide (PACAP) acts as a local factor in the ovary of mammals. In nonmammalian vertebrates, although the expression of PACAP has also been demonstrated in the ovary, the information on its functions and regulation is limited. In the present study, we identified a new type of PACAP, zebrafish (zf)PACAP38-2, from the zebrafish ovary. The precursor of GHRH-zfPACAP38-2 consists of 175 amino acids with only 64% homology with another type of zebrafish PACAP, zfPACAP38-1. RT-PCR analysis detected two messengers of zfPACAP38-2 in the zebrafish ovary. The short product was more abundant, and it encodes zfPACAP38-2 only, whereas the long form codes for both zfPACAP38-2 and GHRH. Using a primary culture of zebrafish follicle cells, we demonstrated that gonadotropin (human chorionic gonadotropin and goldfish pituitary extract) significantly stimulated zfPACAP38-2 expression within 2 h; however, the effect decreased to the control level after 8 h of treatment. The stimulation of zfPACAP38-2 expression by gonadotropin could be mimicked by cAMP analogs and forskolin but suppressed by H89 (10 mum), suggesting the involvement of the cAMP-protein kinase A signaling pathway. We also examined the expression of PACAP receptor VPAC2-R in the zebrafish ovary. Unlike zfPACAP38-2, which showed a trend of increase during follicle development, the expression of VPAC2-R mRNA in the follicles showed no significant stage-dependent variation, and its expression in the follicle cells did not respond to gonadotropin treatment. Our studies further demonstrated that synthetic zfPACAP38-2 stimulated oocyte maturation and increased the expression of follistatin in zebrafish ovarian follicle cells. These results suggest that zfPACAP38-2 is a potential ovarian factor that mediates gonadotropin actions in paracrine/autocrine manners, and its functional roles are likely, to some extent, related to the ovarian activin/follistatin system.
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PMID:Cloning, regulation of messenger ribonucleic acid expression, and function of a new isoform of pituitary adenylate cyclase-activating polypeptide in the zebrafish ovary. 1295 88


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