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)

Ca2+ fluxes were examined in HEK 293 cells stably expressing the rat or porcine calcitonin receptors (CTRs). Calcitonin (CT) rapidly increased cytosolic Ca2+ ([Ca2+]i) concentrations in these cells in a manner which was sustained in the presence of extracellular Ca2+ ([Ca2+]e). In cells pretreated with CT, elevation of the [Ca2+]e concentration resulted in a further increase in [Ca2+]i which was concentration-dependent with respect to both the concentration of CT and the increment of [Ca2+]e. Untransfected cells, cells transfected with vector alone, and CTR-transfected cells not treated with CT, were unresponsive to [Ca2+]e. The microsomal Ca(2+)-ATPase inhibitor thapsigargin was able to mimic both the acute [Ca2+]i fluxes and responsiveness to [Ca2+]e mediated by CT in these cells. The CT-induced responsiveness to [Ca2+]e was neither mimicked by, nor affected by, activators of the cAMP or protein kinase C pathways. Treatment of cells with pertussis toxin influenced neither the primary Ca2+ fluxes in response to CT or thapsigargin nor the agonist-induced [Ca2+]e influx. Nifedipine failed to block responses to either CT or thapsigargin. These results lead to the important conclusion that the CTR participates in receptor-activated Ca2+ inflow, in which depletion of intracellular Ca2+ pools leads secondarily to influx of extracellular Ca2+.
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PMID:Calcium inflow in cells transfected with cloned rat and porcine calcitonin receptors. 769 52

Calcitonin gene-related peptide (CGRP) immunoreactivity was detected at day 2 in vitro (embryonic day 15) in developing mouse dorsal root ganglion (DRG) neurons in primary culture. During 2 weeks of culture the proportion of CGRP-immunoreactive (CGRP-IR) neurons remained around 65-70%, much higher than usually found in adult animals (45-50%). Treatment of cultures with the capsaicin analog resiniferatoxin (RTX; 0.3-30 nM) significantly augmented CGRP immunoreactivity per neuron at all ages investigated without increasing the number of CGRP-immunoreactive cells. The increased CGRP immunoreactivity was observed both in the axonal varicosities and in the perinuclear region of cell bodies. This RTX-induced increase in CGRP immunoreactivity was completely blocked by Ruthenium red (RR). Treatment with the non-esterified form of RTX (resiniferol 9, 13, 14 orthophenylacetate, ROPA) produced no increase. These results suggest that: (1) early expression of the CGRP phenotype is regulated in a cell-autonomous way in developing mouse DRG neurons in vitro; and (2) the RTX-induced increase in CGRP biosynthesis is most likely the result of activating the capsaicin/RTX receptor rather than directly activating the protein kinase C (PKC) pathway in vitro. The results may also reflect qualitative and quantitative differences in capsaicin/RTX sensitivity of sensory neurons between embryonal and adult ages.
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PMID:The calcitonin gene-related peptide (CGRP) phenotype is expressed early and up-regulated by resiniferatoxin (RTX) in mouse sensory neurons. 795 56

The regulation of expression of parathyroid hormone-related protein (PTHRP) mRNA by protein kinase C and cyclic-AMP-dependent pathways was studied in a human lung cancer cell line (BEN). PTHRP mRNA was increased by agents which activate protein kinase C, but not by those which activate cyclic-AMP-dependent pathways. Activators of both second messenger pathways stimulated a dose-dependent increase in the accumulation of PTHRP in conditioned medium assayed using sensitive region-specific immunoassays for PTHRP1-34 and 1-86. Calcitonin had a dose-dependent effect on the accumulation of PTHRP in culture medium which may be mediated via cyclic AMP. Varying the calcium concentration from 0-2.5 mM had no effect on peptide secretion over 20 h, while short-term incubation (30 min) with ionomycin (2.5-75 micrograms/ml) significantly increased PTHRP immunoreactivity in the medium.
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PMID:Expression and secretion of parathyroid hormone-related protein by a human cancer cell line. 831 63

Calcitonin gene-related peptide (CGRP), a neuropeptide localized in the cardiac autonomic nervous supply, shares 46% similarity in sequence of amino acids with amylin, a peptide synthesized in pancreatic beta-cells. In the present study, the question was addressed whether these peptides could exert hypertrophic effects in cardiomyocytes isolated from the ventricles of adult rats and maintained in short-term, serum-free primary culture. FCS (10% v/v), employed as a positive control, increased the incorporation of l-[14C]phenylalanine into cellular protein, total content of cellular RNA and total mass of cellular protein significantly. CGRP and amylin also increased each of these parameters significantly and in a concentration-dependent manner; maximum responses occurred at 100 pM and 10 nM for CGRP and amylin, respectively. The selective antagonist at CGRP1-receptors, CGRP8-37(100 nM), inhibited significantly the incorporation of l-[14C] phenylalanine into cellular protein in response to CGRP and amylin. The selective inhibitor of protein kinase C (PKC), bisindolylmalemide (BIM) (5 microM), reduced significantly the incorporation of l-[14C] phenylalanine into cellular protein in response to phenylephrine (1 microM), employed as a positive control, but did not inhibit the response to insulin (1 unit/ml), employed as a negative control. BIM (5 microM) reduced significantly the responses to FCS (10% v/v), amylin (10 nM) and CGRP (10 pM), but did not inhibit the response to CGRP (100 pM). The activity of protein kinase C in membranes prepared from intact myocytes pre-treated for 10 min with the phorbol ester, phorbol 12-myristate 13-acetate (PMA) (100 nM), employed as a positive control, and CGRP (10 pM) was significantly greater than in membranes prepared from cardiomyocytes not subjected to agonist stimulation. Phenylephrine (1 microM) increased significantly the specific activity of creatine kinase but not of lactate dehydrogenase in day 1 cultures of freshly isolated cardiomyocytes. Significant induction of creatine kinase, but not lactate dehydrogenase, was also stimulated by CGRP and amylin; the maximum responses occurred at 100 pM and 100 nM CGRP and amylin, respectively. In conclusion, CGRP and amylin exert hypertrophic effects directly on ventricular cardiomyocytes from the hearts of adult rats in vitro. These effects are: (1) due to de novo protein synthesis since total content of cellular RNA and incorporation of l-[14C]phenylalanine into cellular protein were also increased; (2) mediated by a common population of CGRP1-preferring receptors at which amylin binds with lower potency: (3) mediated, at least partly, by the activation of PKC; (4) may be associated with a fetal shift in gene expression, characterized by selective induction of creatine kinase.
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PMID:Hypertrophic effects of calcitonin gene-related peptide (CGRP) and amylin on adult mammalian ventricular cardiomyocytes. 859 94

Calcitonin gene-related peptide (CGRP) added to the internal fluid bathing the isolated skin of Rana esculenta strongly stimulates the active sodium absorption. This action is dose-dependent, the dose eliciting the maximal effect being 2 . 10(-7) M; alpha and beta CGRP exhibit the same potency. The CGRP action on sodium transport is mainly due to its interaction with CGRP1 receptors, since it is inhibited by CGRP8-37, its specific antagonist. The second messengers probably involved in the action of CGRP are cAMP and Ca+2, since this action is reduced by SQ22536 and W7, which are inhibitors of adenyl cyclase and calmodulin respectively. On the contrary, inhibitors of protein kinase C (1-O-hexadecyl-2-O-methyl-sn-glycerol) and nitric oxide synthase (L-NAME) do not modify the action on sodium transport. ETYA, an inhibitor of all the metabolic pathways of arachidonic acid, decreases the CGRP action by 38%. In order to search for the arachidonic acid metabolites involved in the CGRP action, the effect of the following inhibitors was tested: aspirin and naproxen (for cyclooxygenases), NDGA (for cyclooxygenases), NDGA (for lipoxygenases) clotrimazole (for epoxygenases). None of these substances is able to inhibit the CGRP action on sodium transport. Moreover, adding arachidonic acid inhibits the CGRP action, but this effect was also obtained by another unsaturated fatty acid, oleic acid. Since unsaturated fatty acids are able to inhibit the protein kinase A, these results indirectly support the role of cAMP as a second messenger of the CGRP action on sodium transport.
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PMID:Effect of calcitonin gene-related peptide on sodium absorption through isolated skin of Rana esculenta. 881 96

Neuronal factors co-released with neurotransmitters may play an important role in synapse development and function. Calcitonin gene related peptide (CGRP) and adenosine 5'-triphosphate (ATP), two principal neuromodulators present in the motor nerve terminals, were studied for their roles and mechanisms during early development of neuromuscular synapses in Xenopus nerve--muscle co-cultures. CGRP treatment increased the decay time and amplitude of spontaneous synaptic currents (SSCs) recorded from innervated myocytes, without affecting SSC frequency, suggesting a postsynaptic mechanism. ATP also increased the SSC amplitude and decay time. In addition, ATP was shown to potentiate the responses of isolated myocytes to iontophoretically applied acetylcholine (ACh). Single-channel recording from isolate myocytes showed that both CGRP and ATP specifically increased the open time of embryonic-type, low-conductance ACh channels. Pharmacological experiments suggest that the CGRP actions were mediated by cAMP-dependent protein kinase (PKA), while ATP exerted its effects by binding to P2 purinoceptors and thereby activating protein kinase C (PKC). Moreover, the effects of CGRP and ATP on ACh channel activity were restricted to immature myocytes. Taken together, these results suggest that endogenous CGRP and ATP co-released with ACh from the nerve terminal may promote synaptic development by potentiating postsynaptic ACh channel activity during the early phase of synaptogenesis.
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PMID:Regulation of postsynaptic responses by calcitonin gene related peptide and ATP at developing neuromuscular junctions. 884

Calcitonin is known to inhibit osteoclastic bone resorption through its receptor, which is abundantly expressed on the plasma membrane of osteoclasts. Recently, it was reported that calcitonin receptors were coupled to both cAMP-dependent protein kinase (PKA) and protein kinase C (PKC). To examine how the PKA and PKC pathways are involved in the effects of calcitonin, we focused on changes in the cytoskeleton of murine osteoclast-like multinucleated cells (OCLs) formed in vitro. When OCLs were cultured on dentine slices, they formed resorption pits and ringed structures of F-actin dots (actin rings). Elcatonin, a synthetic analogue of eel calcitonin, disrupted actin rings and inhibited pit formation in a dose-dependent manner. Forskolin and dibutyryl cAMP, both of which have the ability to activate PKA, mimicked the effects of elcatonin. Phorbol myristate acetate and phorbol 12,13-dibutyrate, both of which have the ability to activate PKC, also inhibited pit-forming activity, but little affected actin rings of OCLs. The inhibitory effects of elcatonin on the pit formation and actin ring formation were partially restored by the treatment with Rp-cAMPs, a cAMP antagonist. Elcatonin induced a rapid increase in PKA activity within a few minutes, and its activation by elcatonin occurred in a dose-dependent manner. The time- and dose-dependent profiles of elcatonin for the activation of PKA were similar to those for the disruption of actin rings. Moreover, microinjection of activated PKA into OCLs disrupted actin rings within 10 min on culture dishes. Actin rings were little affected by the microinjection of the PKA preincubated with a cAMP-dependent protein kinase inhibitor (IP-20) into OCLs. These results suggest that PKA activation, rather than PKC activation, is involved in mediating the effects of calcitonin, through the disruption of actin organization.
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PMID:Calcitonin-induced changes in the cytoskeleton are mediated by a signal pathway associated with protein kinase A in osteoclasts. 889 34

Tumour necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) are potent inflammatory cytokines produced by osteoblasts and whose contribution to bone loss occurring in oestrogen deficiency is well documented. Calcitonin gene-related peptide (CGRP) is a neuropeptide abundantly concentrated in sensory nerve endings innervating bone metaphyses and periosteum suggesting that it controls bone homeostasis locally. Since CGRP was shown to inhibit TNF-alpha production by T cells and stimulate IL-6 expression by fibroblasts, this study was designed to investigate whether CGRP regulated TNF-alpha and IL-6 production by osteoblasts. We show that CGRP inhibits the production of TNF-alpha by both lipopolysaccharide (LPS)- and IL-1-stimulated fetal rat osteoblasts. Like CGRP, the cAMP agonists prostaglandin E2 (PGE2), dibutyryl cAMP (Bt2cAMP) and forskolin inhibit TNF-alpha production by osteoblasts. Exposure of osteoblasts to a high dose of phorbol myristoyl acetate (PMA) to deplete PKC activity abolished CGRP-mediated TNF-alpha suppression. In contrast with its potent inhibition of TNF-alpha production, we show that CGRP is a weak inducer of IL-6 when compared to PGE2, Bt2cAMP and forskolin. However, in presence of isobutylmethylxanthine (IBMX) CGRP stimulates the production of IL-6. Collectively, these data suggest that the inhibition of TNF-alpha CGRP is cAMP dependent and PMA sensitive and that the concentration of intracellular cAMP may be a regulatory mechanism for IL-6 expression in osteoblasts.
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PMID:The neuropeptide calcitonin gene-related peptide inhibits TNF-alpha but poorly induces IL-6 production by fetal rat osteoblasts. 941 11

The action of adenosine-5'-O-(2-thiodiphosphate), a non-hydrolysable purine analogue and potent P2Y1-purinoceptor agonist, was studied on immediate early gene expression in rat astrocyte cultures. A rapid and transient increase in c-fos, junB, c-jun and Tis11 messenger RNA was observed in cultured astrocytes after treatment with adenosine-5'-O-(2-thiodiphosphate). Maximal induction of immediate early gene expression was obtained within 30 min of stimulation and c-fos was the most sensitive indicator of P2Y-purinoceptor activation. Calcitonin gene-related peptide has also been shown to be a potent inducer of c-fos messenger RNA in cultured astroglial cells. The combined stimulation of astrocytes with calcitonin gene-related peptide and adenosine-5'-O-(2-thiodiphosphate) resulted in the potentiated expression of c-fos messenger RNA. The superinduction of immediate early gene expression by calcitonin gene-related peptide and extracellular ATP in cultured astrocytes might result from intracellular signal transduction cross-talk, since adenosine-5'-O-(2-thiodiphosphate) was found to increase calcitonin gene-related peptide-induced cyclic AMP accumulation by 35%. Phorbol 12-myristate 13-acetate also increased calcitonin gene-related peptide-evoked cyclic AMP accumulation and led to the induction of immediate early gene expression, suggesting that protein kinase C might be at least in part involved in purinergic cross-talk. Our results demonstrate synergistic roles for extracellular ATP and calcitonin gene-related peptide in the transcriptional activation of astroglial cells.
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PMID:Stimulation of P2Y-purinoceptors on astrocytes results in immediate early gene expression and potentiation of neuropeptide action. 962 49

While it is well established that adenylyl cyclase and phospholipase C-beta are two proximal signal effectors for the calcitonin receptor, the more distal signaling pathways are less well characterized. G protein-coupled receptors can activate Erk1/2 by Gs-, Gi-, or Gq-dependent signaling pathways, depending on the specific receptor and cell type examined. Since the calcitonin receptor can couple to all three of these G proteins, the ability of calcitonin to activate Erk1/2 was investigated. Calcitonin induced time- and concentration-dependent increases in Shc tyrosine phosphorylation, Shc-Grb2 association and Erk1/2 phosphorylation and activation in a HEK 293 cell line that stably expresses the rabbit calcitonin receptor C1a isoform. Pertussis toxin, which inactivates Gi, and calphostin C, a protein kinase C inhibitor, each partially inhibited calcitonin-induced Shc tyrosine phosphorylation, Shc-Grb2 association, and Erk1/2 phosphorylation. In contrast, neither forskolin nor H89, a protein kinase A inhibitor, had a significant effect on basal or calcitonin-stimulated Erk1/2 phosphorylation. Our results suggest that the calcitonin receptor induces Shc phosphorylation and Erk1/2 activation in HEK293 cells by parallel Gi- and PKC-dependent mechanisms. The calcitonin-induced elevation of cytosolic free Ca2+ was required for Erk1/2 phosphorylation, since preventing any change in cytosolic free Ca2+ by chelating both cytosolic and extracellular Ca2+ abolished the response. However, the change in Ca2+ that is induced by calcitonin is not sufficient to account for the calcitonin-induced Erk1/2 phosphorylation, since treatment with 100 nM ionomycin or 10 microM thapsigargin, each of which induced elevations of Ca2+ comparable to those induced by calcitonin, induced significantly less Erk1/2 phosphorylation than that induced by calcitonin. Erk1/2 may have important roles as downstream effectors mediating cellular responses to calcitonin stimulation.
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PMID:The calcitonin receptor stimulates Shc tyrosine phosphorylation and Erk1/2 activation. Involvement of Gi, protein kinase C, and calcium. 967 14


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