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

---

Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It was previously shown that hormone receptor coupling to voltage-dependent calcium channels in prolactin and growth hormone-producing GH(3) cells was heavily dependent on the specific heterotrimeric combinations of alpha, beta, and gamma subunits of the guanosine triphosphate (GTP)-binding protein family. Consequently, we assessed whether this was also the case for hormonal modulation of the adenylate cyclase (AC) and phospholipase C (PL-C) effector enzymes in GH(3) cells in culture. By employing polyclonal antibodies directed towards C-terminal decapeptides of various alpha subunits in membrane assays, as well as antisense oligonucleotides towards certain beta- and gamma-subunit genes in whole-cell incubations, it was possible to unravel a tentative profile of heterotrimers preferred by some of the seven-transmembrane-stretch receptors in their modulation of AC and PL-C activities. Vasoactive intestinal peptide (VIP) and thyroliberin (TRH) activate membrane-bound AC through alpha(s)beta(2)gamma(2), while somatostatin (SRIH) and dopamine (DA) inhibited the AC through alpha(i2)beta(1)gamma(3). TRH activated membrane-bound PL-C through alpha(q/11)beta(4)gamma(2), while DA inhibition of the PL-C was accomplished via alpha(o)beta(3)gamma(4). Hence, it seems that not only the specificity of alpha subunits determines the coupling between G protein-associated receptors in GH cells, the receptor binding to G proteins also requires certain combinations of beta and gamma subunits.
...
PMID:Specific combinations of G-protein subunits discriminate hormonal signalling in rat pituitary (GH(3)) cells in culture. 1130 42

In this investigation, we studied the effects of Momany peptide (GHRP-5), on somatotroph secretory activity. Acute and chronic administration of GHRP-5 provokes a significant release of growth hormone that can be closely correlated with ultrastructural changes in somatotroph populations. After 3,5 and 7 days of GHRP-5 treatment, two somatotroph cell subpopulations coexist. One of them has an enhanced secretory activity and the other presents a quiescent appearance. Therefore, pituitary growth hormone content was not affected in the first seven days of GHRP-5 treatment. After 14 days, there was a significant depletion of growth hormone pituitary content coincident with the highest levels of serum growth hormone. These results concur with the surge of a new hyperactive somatotroph subtype characterised by numerous immature secretory granules that are discharged bypassing the maturation step. Acute and chronic treatments caused no changes in somatotroph cell density, the area immunostained for growth hormone and the levels of total mRNA for transcription factor pit-1. The results of pituitary cell cultures incubated with specific blockers for different signalling pathways demonstrated an involvement of the phospholipase C-inositol phosphate system in GHRP-5 stimulated somatotroph secretion. GHRP-5 treatment enhanced significantly the release of growth hormone, thereby eliciting ultrastructural modifications in somatotrophs that can be correlated with an increased secretory activity devoid of cell density changes.
...
PMID:Behaviour of a somatotroph population under a growth hormone releasing peptide treatment. 1219 76

The regulation of the synthesis and secretion of human growth hormone (hGH), its biologic activity, and its therapeutic use are reviewed. Both the production and secretion of GH are stimulated by hypothalamic GH-releasing hormone (GHRH) and by the endogenous GH secretagogue (GHS) ghrelin, a product of the oxyntic cells located within the fundus of the stomach. Ghrelin and GHRH act synergistically to stimulate GH secretion when administered in vivo, but they act additively when incubated with somatotrophs in vitro. Ghrelin is also found within the hypothalamic arcuate nucleus where it may enhance the release of GHRH and impair that of somatostatin (SRIH) thus contributing to its synergism with GHRH; ghrelin is an orexigenic peptide as well as a GHS and appears to play an important role in energy metabolism. SRIH inhibits the secretion but not the synthesis of GH and more effectively that stimulated by GHRH than that by ghrelin. The action of GH is mediated by the GH receptor, a straight chain protein of 620 amino acids with extracellular, transmembrane and cytoplasmic domains. GH has two specific receptor binding sites, (I, II) that bind sequentially to similar acceptor sequences of two GHRs. Activation of the GHR signal transduction pathway begins with attachment of two Janus kinase 2 (JAK2) molecules to the intracellular domains of the GHRs leading to phosphorylation of the tyrosine residues of JAK2 and the GHRs; thereafter the signal transduction and activators of transcription (STAT) and Ras mitogen-activated-protein kinase pathways are enhanced. GHRH, SRIH, and ghrelin act through G-protein coupled receptors (GPCR); GHRH activates adenylyl cyclase, cyclic AMP, and protein kinase A pathways, while ghrelin stimulates phospholipase C activity leading to production of inositol 1,4,5-trisphophate and diacylglycerol, increase in cytosolic calcium levels, and GH release; SRIH acts though an inhibitory GPCR to prevent depolarization of the somatotroph thus blocking GH secretion. GH has long been used to stimulate linear growth in children with GH deficiency (GHD); it has also been demonstrated to be effective in adults with GHD. The availability of large quantities of recombinant hGH has broadly increased the number of children with short stature being treated with this agent--not always with marked effectiveness. Synthesis of the GHR antagonist pegvisomant has provided another agent with which to treat patients with acromegaly. GHRH also enhances linear growth rate effectively in children with GHD but is less effective than hGH. The discovery of peptidyl and non-peptidyl GH secretagogues (that preceded and led to the identification of ghrelin itself) presents yet other agents for stimulation of endogenous GH secretion that have been useful in diagnostic studies for GHD and for its treatment in small groups of subjects. It is likely that hGH and its secretagoguess will become of increasing clinical usefulness in future decades.
...
PMID:Clinical pharmacology of human growth hormone and its secretagogues. 1247 95

Pituitary adenylate cyclase-activating polypeptide (PACAP) has been conserved remarkably during evolution and is widely expressed in the nervous system across phyla. PACAP has an amino acid sequence homology of 68% with that of vasoactive intestinal polypeptide (VIP) and of 37% with that of secretin, indicating that PACAP is a member of the VIP/glucagon/secretin superfamily. PACAP exerts its actions via three heptahelical G-protein-linked receptors: one PACAP-specific (PAC1) receptor and two receptors (VPAC1 and VPAC2) shared with VIP. PACAP stimulates several different signaling cascades in neurons, leading to the activation of adenylate cyclase, phospholipase C, and mitogen-activated protein kinase and mobilization of calcium. Although PACAP and VIP have no apparent homology with calcitonin and parathyroid hormone (PTH), PAC1, VPAC, secretin, glucagon, glucagon-like peptide 1, growth hormone-releasing hormone, calcitonin, and PTH/PTH-related peptide receptors are related to each other and constitute a subfamily of the G-protein-coupled receptors. Distribution analysis of PACAP and its receptors and pharmacological studies have elucidated its pleiotropic effects in the central and peripheral nervous systems. However, the relevance of the pharmacological PACAP effects to the actual physiological activities of endogenous PACAP has not been addressed, because potent and selective low-molecular-weight PACAP antagonists have not yet been developed. To assess the function of PACAP in vivo, we have recently generated PAC1 receptor- and PACAP-targeted mice, and provided evidence that PACAP plays a previously uncharacterized role in the regulation of psychomotor behaviors. In this review, we focus on the physiological and or pathophysiological roles mediated by PACAP in the nervous system.
...
PMID:[Physiological significance of pituitary adenylate cyclase-activating polypeptide (PACAP) in the nervous system]. 1251 Mar 88

(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.
...
PMID:Growth hormone secretagogues modulate the electrical and contractile properties of rat skeletal muscle through a ghrelin-specific receptor. 1278 17

Research on the mechanism for growth hormone secretagogue (GHS) induction of growth hormone secretion led to the discovery of the GHS receptor (GHS-R) and later to ghrelin, an endogenous ligand for GHS-R. The ability of ghrelin to induce an increase in the intracellular Ca(2+) concentration - [Ca(2+)](i) - in somatotropes was examined in dispersed porcine pituitary cells using a calcium imaging system. Somatotropes were functionally identified by application of human growth hormone releasing hormone. Ghrelin increased the [Ca(2+)](i) in a dose-dependent manner in 98% of the cells that responded to human growth hormone releasing hormone. In the presence of (D-Lys(3))-GHRP-6, a specific receptor antagonist of GHS-R, the increase in [Ca(2+)](i) evoked by ghrelin was decreased. Pretreatment of cultures with somatostatin or neuropeptide Y reduced the ghrelin-induced increase of [Ca(2+)](i). The stimulatory effect of ghrelin on somatotropes was greatly attenuated in low-calcium saline and blocked by nifedipine, an L-type calcium channel blocker, suggesting involvement of calcium channels. In a zero Na(+) solution, the stimulatory effect of ghrelin on somatotropes was decreased, suggesting that besides calcium channels, sodium channels are also involved in ghrelin-induced calcium transients. Either SQ-22536, an adenylyl cyclase inhibitor, or U73122, a phospholipase C inhibitor, decreased the stimulatory effects of ghrelin on [Ca(2+)](i) transiently, indicating the involvement of adenylyl cyclase-cyclic adenosine monophosphate and phospholipase C inositol 1,4,5-trisphosphate pathways. The nonpeptidyl GHS, L-692,585 (L-585), induced changes in [Ca(2+)](i) similar to those observed with ghrelin. Application of L-585 after ghrelin did not have additive effects on [Ca(2+)](i). Preapplication of L-585 blocked the stimulatory effect of ghrelin on somatotropes. Simultaneous application of ghrelin and L-585 did not cause an additive increase in [Ca(2+)](i). Our results suggest that the actions of ghrelin and synthetic GHS closely parallel each other, in a manner that is consistent with an increase of hormone secretion.
...
PMID:Stimulatory effect of ghrelin on isolated porcine somatotropes. 1284 23

We have recently cloned the full-length cDNAs of the two growth hormone secretagogue receptor (GHSR) subtypes from a teleost species, the black seabream (Acanthopagrus schlegeli) [Mol. Cell. Endocrinol. 214 (2004) 81], namely sbGHSR-1a and sbGHSR-1b. Functional expression of these two receptor constructs in human embryonic kidney 293 (HEK293) cells indicated that stimulation of sbGHSR-1a by growth hormone secretagogues (GHS) could evoke increases in intracellular Ca2+ concentration ([Ca2+]i), whereas sbGHSR-1b appeared to play an inhibitory role on the signal transduction activity of sbGHSR-1a. In the present study, we have further investigated the signal transduction mechanism of sbGHSR-1a. The peptide GHS GHRP-6 and the non-peptide GHS L163,540 were able to trigger a receptor specific and phospholipase C (PLC)-dependent elevation of [Ca2+]i in HEK293 cells stably expressing sbGHSR-1a. This GHS-induced calcium mobilization was also dependent on protein kinase C activated L-type calcium channel opening. It was found that sbGHSR-1a could function in an agonist-independent manner as it exhibited a high basal activity of inositol phosphate production in the absence of GHS, indicating that the fish receptor is constitutively active. In addition, the extracellular signal-regulated kinases 1 and 2 (ERK1/2) were found to be activated upon stimulation of sbGHSR-1a by GHRP-6. This observation provides direct evidence in the coupling of sbGHSR-1a to ERK1/2 activation. Neither Gs nor Gi proteins are coupled to the receptor, as GHS did not induce cAMP production nor inhibit forskolin-stimulated cAMP accumulation in the sbGHSR-1a bearing cells. Furthermore, the ability of the GHSR antagonist D-Lys3-GHRP-6 to inhibit basal PLC and basal ERK1/2 activity suggests that this compound is an inverse agonist. In summary, the sbGHSR-1a appears to couple through the G(q/11)-mediated pathway to activate PLC, resulting in increased IP3 production and Ca2+ mobilization from both intracellular and extracellular stores. Moreover, sbGHSR-1a may trigger multiple signal transduction cascades to exert its physiological functions.
...
PMID:Signal transduction mechanism of the seabream growth hormone secretagogue receptor. 1552 76

To understand the role of growth hormone-releasing hormone (GHRH) and pituitary adenylate cyclase-activating polypeptide (PACAP) and to examine the functional significance of the co-expression of GHRH and PACAP in fish, their receptors were characterized in zebrafish. Three cDNAs encoding the PAC(1) receptor, the VPAC(1) receptor, and the partial GHRH receptor were identified from zebrafish. Functional expression of the PAC(1) and VPAC(1) receptors revealed that both are potently coupled to the adenylyl cyclase pathway, but only the PAC(1) receptor is coupled to the phospholipase C pathway. Transcripts for all three receptors were widely distributed, often in an overlapping pattern in the adult zebrafish. Also, one splice variant of the partial GHRH receptor and three splice variants of the PAC(1) receptor were identified from adult zebrafish. The long GHRH receptor transcript contained a 27 amino acid insert in transmembrane domain 5 encoding a premature stop codon leading to a truncated receptor protein. For the PAC(1) receptor, two of the splice variants corresponded to the hop1 and hop2 variants characterized in mammals. The third splice variant identified from the gill encoded a novel 107 bp insert containing a premature stop codon. Therefore, PACAP and GHRH have widespread, overlapping target sites suggesting a coordinated role for these hormones in evolution.
...
PMID:Characterization of four receptor cDNAs: PAC1, VPAC1, a novel PAC1 and a partial GHRH in zebrafish. 1571 35

In broad terms, there are 3 types of cardiac hypertrophy: normal growth, growth induced by physical conditioning (i.e., physiologic hypertrophy), and growth induced by pathologic stimuli. Recent evidence suggests that normal and exercise-induced cardiac growth are regulated in large part by the growth hormone/IGF axis via signaling through the PI3K/Akt pathway. In contrast, pathological or reactive cardiac growth is triggered by autocrine and paracrine neurohormonal factors released during biomechanical stress that signal through the Gq/phospholipase C pathway, leading to an increase in cytosolic calcium and activation of PKC. Here we review recent developments in the area of these cardiotrophic kinases, highlighting the utility of animal models that are helping to identify molecular targets in the human condition.
...
PMID:Protein kinase cascades in the regulation of cardiac hypertrophy. 1576 34

The involvement of intracellular Ca(2+) stores and their regulatory mechanisms in mediating pituitary adenylate cyclase-activating polypeptide (PACAP) stimulation of growth hormone (GH) and maturational gonadotrophin (GTH-II) secretion from goldfish pituitary cells was investigated using a cell column perifusion system. Pretreatment with caffeine abolished the GH and GTH-II responses to PACAP. Dantrolene attenuated PACAP-elicited GTH-II release but did not affect the GH response, whereas ryanodine and 8-bromo-cADP ribose did not alter PACAP-induced GH and GTH-II release. Two endoplasmic/sarcoplasmic reticulum Ca(2+) ATPase (SERCA) inhibitors, thapsigargin and cyclopiazonic acid, augmented PACAP-induced GTH-II release; similarly, thapsigargin elevated GH responses to PACAP. Treatment with carbonyl cyanide m-chlorophenylhydrazone, a mitochondrial uncoupler, reduced PACAP-stimulated GH release; however, inhibition of the mitochondrial Ca(2+) uniport by Ru360 did not affect GH and GTH-II responses. The phosphatidyl inositol (PI)-specific phospholipase C (PLC) inhibitor ET-18-OCH(3) inhibited, whereas the phosphatidyl-choline (PC)-specific PLC inhibitor D609 enhanced, PACAP-stimulated GH and GTH-II responses. On the other hand, the IP(3) receptor blocker xestospongin D had no effect on PACAP-induced GTH-II response and potentiated the GH response. These results suggest that, despite some differences between GH and GTH-II cells, PACAP actions in both cell types generally rely on a caffeine-sensitive, but a largely ryanodine receptor-independent, mechanism. PC-PLC and some SERCA negatively modulate PACAP actions but mitochondrial Ca(2+) stores per se are not important. A novel PI-PLC mechanism, which does not involve the traditional IP(3)/Ca(2+) pathway, is also suggested.
...
PMID:Intracellular calcium involvement in pituitary adenylate cyclase-activating polypeptide stimulation of growth hormone and gonadotrophin secretion in goldfish pituitary cells. 1592 41


<< Previous 1 2 3 4 Next >>

---