Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth hormone (GH) and insulin-like growth factor I (IGF-I) exert a variety of actions in renal tissue. To shed light upon the renal GH-IGF I axis we have characterized the cell biology of GH and IGF I in two parts of the nephron that are targets for these peptides, proximal tubule and collecting duct. Receptors for both GH and IGF I are present in the basolateral membrane of the renal proximal tubular cell. GH activates phospholipase C and IGF I stimulates phosphorylation of its receptor at this site. Both peptides directly enhance gluconeogenesis in proximal tubule. GH stimulates IGF I gene expression in collecting duct. IGF I of collecting duct origin could act as a paracrine growth factor in other portions of the nephron. IGF I may be causative of renal hypertrophy that occurs in the settings of hypersomatotropism, unilateral nephrectomy (compensatory hypertrophy) and diabetes mellitus.
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PMID:Renal cellular biology of growth hormone and insulin-like growth factor I. 165 79

Growth hormone (GH) is required for the terminal differentiation of preadipose Ob1771 cells that have entered the differentiation program as evidenced by the expression of early marker genes (pOb24 and lipoprotein lipase). Induction of c-fos mRNA within 15 min and induction of insulin-like growth factor I mRNA within a few hours take place in response to GH. The role of GH is mediated, at least in part, by means of the activation of protein kinase C, as shown by the inhibition of epidermal growth factor binding and by the expression of the c-fos gene, and is thus analogous to the action of prostaglandin F2 alpha and 4 beta-phorbol-12,13-didecanoate in this respect. However, in contrast to that of the c-fos gene, the regulation of insulin-like growth factor I gene expression by GH is not mediated by means of the activation of protein kinase C, and, in line with this, prostaglandin F2 alpha and 4 beta-phorbol-12,13-didecanoate were ineffective. GH and prostaglandin F2 alpha were able to stimulate the formation of diacyglycerol within a few seconds, but GH did not elicit an accumulation of inositol phosphates, in contrast to that generated by prostaglandin F2 alpha. We conclude that the transduction signal of GH action in c-fos mRNA induction is the formation of diacylglycerol and that the mechanism whereby GH can activate protein kinase C is associated with a phospholipase C-mediated hydrolysis of glycerophospholipids other than inositol phospholipids.
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PMID:Growth hormone stimulates c-fos gene expression by means of protein kinase C without increasing inositol lipid turnover. 249 51

Growth hormone (GH; 500 ng/ml) rapidly doubled cytosolic free Ca2+ concentration ([Ca2+]i) in rat adipocytes as determined with the Ca2+ indicator fura 2. No response was seen in Ca(2+)-free medium, suggesting that the increase in [Ca2+]i was due to Ca2+ influx. GH also doubled the influx of Mn2- as inferred from the rate of fluorescence quenching. Depolarization with 30 mMK+ also increased [Ca2+]i, and the increase in [Ca2+]i due to either GH or 30 mMK+ was blocked by 100 nM nimodipine, suggesting that GH increases [Ca2+]i by activating voltage-sensitive L-type Ca2+ channels. GH increased [Ca2+]i even when K+ channels were blocked, suggesting that activation of Ca2+ uptake was not secondary to closure of K+ channels and consequent depolarization. A diacylglycerol (PAG) analogue, 1,2-dioctanoyl-sn-glycerol (50 microM), duplicated, and the protein kinase C(PKC) inhibitors calphostin C (100 nM), chelerythrine (1 microM), and bis-indolylmaleimide (250 nM) inhibited the effects of GH on [Ca2+]i. Xanthogenate tricyclodecan-9-yl (D609), a specific inhibitor of phospholipase C(PLC), abolished the increase in [Ca2+]i due to GH but not to DAG. The results suggest that GH increases [Ca2+]i by activation of PLC, release of DAG, and activation of a Ca(2+)-independent isoform of PKC. PKC-catalyzed phosphorylation of either the Ca2+ channels or a protein that regulates them may account for the influx of Ca2+ produced by GH.
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PMID:Growth hormone increases calcium uptake in rat fat cells by a mechanism dependent on protein kinase C. 896 51

Growth hormone (GH) is an important mitogenic stimulus for the insulin-producing beta-cell. We investigated the effects of GH on Ca(2+) handling and diacylglycerol (DAG) and cAMP formation in the beta-cell. GH elicited a rapid increase in the cytoplasmic free [Ca(2+)], which required extracellular Ca(2+) and was also blocked by pertussis toxin or protein kinase C (PKC) inhibition. GH also elevated islet DAG content, which should lead to PKC activation. Pertussis toxin and PKC inhibitors obliterated the mitogenicity of GH, suggesting involvement of GTP-binding proteins. PKC activation stimulated beta-cell proliferation, and it also activated phospholipase D. Islet cAMP content was not elevated by GH. Addition of a specific protein kinase A antagonist failed to influence the mitogenicity of GH, whereas a stimulatory cAMP agonist stimulated beta-cell replication. We conclude that GH rapidly increases the beta-cell cytoplasmic free [Ca(2+)] and also evokes a similar increase in DAG content via a phosphatidylcholine-specific phospholipase C, but does not affect mitogen-activated protein kinases, phospholipase D, or the cAMP signaling pathway. This rise in DAG may be of importance in translation of the stimulatory signal of GH into a proliferative response by the beta-cell, which seems to occur through GTP-binding proteins and PKC-dependent mechanisms.
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PMID:Rapid Ca2+ influx and diacylglycerol synthesis in growth hormone-mediated islet beta -cell mitogenesis. 1074

1. Growth hormone (GH) secretion is thought to occur under the reciprocal regulation of two hypothalamic hormones, namely GH-releasing hormone (GHRH) and somatostatin (SRIF), through their engagement with specific cell-surface receptors on the anterior pituitary somatotropes. 2. In addition to GHRH and SRIF, synthetic GH-releasing peptides (GHRP) or GH secretagogue(s) (GHS) regulate GH release through the activation of a novel receptor, the GHS receptor (GHS-R). 3. The cloning of the GHS-R from human, swine and rat identifies a novel G-protein-coupled receptor involved in the control of GH secretion and supports the existence of an undiscovered hormone that may activate this receptor. 4. Varieties of intracellular signalling systems are suggested to mediate the action of GHS, which include changes in intracellular free Ca2+ ([Ca2+]i), cAMP, protein kinases A and C, phospholipase C etc. 5. With regard to the use of signalling systems by GHS, especially a new form of GHRP or GHRP-2, a clear species difference has been demonstrated, supporting the possibility of more than one type of GHS-R.
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PMID:Growth hormone secretagogue actions on the pituitary gland: multiple receptors for multiple ligands? 1083 Dec 31

Cardiac hypertrophy is a major predictor of heart failure and of morbidity and mortality in developed countries. Many hormones and growth factors induce cardiac hypertrophy via activation of members of the phospholipase C (PLC) family. The expression pattern of the PLCbeta isozyme subfamily was investigated in neonatal rat cardiomyocytes after stimulation with different hypertrophic stimuli. Under control conditions and after stimulation with norepinephrine, cardiomyocytes expressed similar amounts of PLCbeta3 mRNA. In the presence of fetal calf serum (FCS), additional expression of PLCbeta1 was induced. Growth hormone (GH) and insulin-like growth factor-I (IGF-I) both induced a substantial increase in PLCbeta3 mRNA expression. The response to GH could not be abolished by the IGF-I receptor blocker IGF-I analogue indicating an IGF-I-independent action of GH. The upregulation of PLCbeta3 by IGF-I was abolished by preincubation of cardiomyocytes with the IGF-I receptor antagonist IGF-I analogue, the tyrosine kinase inhibitor genistein, the extracellular signal-related kinase (ERK) inhibitor PD 98059, the phosphatidylinositol-3- (PI-3) kinase inhibitor wortmannin and the p70 S6 kinase inhibitor rapamycin. Induction of the immediate early genes c-myc, c-fos, and c-jun by IGF-I was abolished by preincubation with antisense oligos against PLCbeta3. It is concluded that the expression of PLCbeta isozymes in cardiomyocytes is differentially regulated by different hypertrophic stimuli. The upregulation of PLCbeta3 by IGF-I is dependent on the activity of tyrosine kinase, ERK, PI3 kinase, and p70 S6 kinase and PLCbeta3 expression seems to be required for the induction of immediate early genes by IGF-I. The involvement of the PLCbeta subfamily in signal transduction of receptors other than G-protein-coupled receptors is suggested.
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PMID:Differential regulation of phospholipase C-beta isozymes in cardiomyocyte hypertrophy. 1094 30

(1) Growth hormone secretagogues (GHS) exhibit potent growth hormone (GH)-releasing activity through the activation of a pituitary receptor. Here, we consider the possibility that GHS can target a specific receptor in rat skeletal muscle and have a role in the control of muscle function. (2) By means of the intracellular microelectrode technique, we found that in vitro application of hexarelin and L-163,255 dose dependently reduced resting chloride (gCl) and potassium (gK) conductances in rat skeletal muscle. These effects were prevented by the GHS-receptor antagonist [D-Lys-3]-GHRP-6, and by either phospholipase C or protein kinase C (PKC) inhibitors. Ghrelin, a natural ligand of GHS receptors, also induced a reduction of muscle gCl and gK, which was antagonised by [D-Lys-3]-GHRP-6. (3) Both GHS shifted the mechanical threshold for the contraction of muscle fibres towards more negative voltages. Accordingly, by means of FURA-2 fluorescent measurements, we demonstrated that L-163,255 induced a resting [Ca(2+)](i) increase, which was reversible and not blocked by nifedipine or removal of external Ca(2+). (4) Ageing is a condition characterised by a deficit of GH secretion, which in turn modifies the electrical and contractile properties of skeletal muscle. In contrast to GH, chronic treatment of aged rats with hexarelin or L-163,255 failed to restore the electrical and contractile muscle properties. Moreover, the two GHS applied in vitro were able to antagonise the beneficial effect on gCl and gK obtained through chronic treatment of aged animals with GH. (5) Thus, skeletal muscle expresses a specific GHS receptor able to decrease gCl and gK through a PKC-mediated intracellular pathway. This peripheral action may account for the lack of restoration of skeletal muscle function in long-term GHS-treated aged animals.
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PMID:Growth hormone secretagogues modulate the electrical and contractile properties of rat skeletal muscle through a ghrelin-specific receptor. 1278 17