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)

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

Serotonin (5-HT) stimulates aldosterone secretion from the rat adrenal gland through 5-HT(7) receptors. The aim of the present study was to investigate the transduction mechanisms associated with activation of 5-HT(7) receptors in rat glomerulosa cells. The stimulatory effect of 5-HT on aldosterone secretion and cAMP formation was significantly reduced by the 5-HT(7) receptor antagonist LY 215840. Pretreatment of cells with the adenylyl cyclase inhibitor SQ 22536 or the PKA inhibitor H-89 markedly attenuated the effect of 5-HT on aldosterone secretion. Conversely, type 2 and 4 phosphodiesterase inhibitors potentiated the 5-HT-induced stimulation of aldosterone secretion. Administration of 5-HT in the vicinity of cultured glomerulosa cells induced a slowly developing and robust increase in cytosolic calcium concentration ([Ca(2+)](i)). The effect of 5-HT on [Ca(2+)](i) was suppressed by mibefradil, a T-type calcium channel blocker. Patch-clamp studies confirmed that 5-HT activated a T-type calcium current. Mibefradil also induced a dose-dependent inhibition of 5-HT-induced aldosterone secretion. The sequence of events associated with activation of 5-HT(7) receptors was investigated. The PKA inhibitor H-89 markedly attenuated both the [Ca(2+)](i) response and the activation of T-type calcium current induced by 5-HT. In contrast, reduction of the calcium concentration in the incubation medium did not affect 5-HT- induced cAMP formation. Preincubation of glomerulosa cells with cholera toxin abolished the stimulatory effect of 5-HT on aldosterone secretion, but pertussis toxin had no effect. Taken together, these data demonstrate that, in rat glomerulosa cells, activation of native 5-HT(7) receptors stimulates cAMP formation through a G(salpha) protein, which in turn provokes calcium influx through T-type calcium channels. Both the adenylyl cyclase/PKA pathway and the calcium influx are involved in 5-HT-induced aldosterone secretion.
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PMID:Activation of 5-HT(7) receptor in rat glomerulosa cells is associated with an increase in adenylyl cyclase activity and calcium influx through T-type calcium channels. 1195 57

Studies from our laboratory have demonstrated rapid ( < 1 min) non-genomic activation of Na(+)-H(+) exchange, K(+) recycling, PKC activity and a PKC-dependent Ca(2+) entry through L-type Ca(2+) channels specifically by mineralocorticoids in distal colon. Aldosterone directly stimulates the activity of the PKC alpha isoform (but not PKC delta, PKC epsilon and PKC zeta) in a cell-free assay system containing only purified commercially available enzyme, appropriate substrate peptide, co-factors and lipid vesicles. The primary ion transport target of the non-genomic signal transduction cascade elicited by aldosterone in epithelia is the Na(+)-H(+) exchanger. In isolated colonic crypts, aldosterone produced a PKC alpha sensitive intracellular alkalinisation within 1 min of hormone addition. Intracellular alkalinisation upregulates an ATP-dependent K(+) channel, which is involved in K(+) recycling to maintain the electrical driving force for Na(+) absorption, while inhibiting a Ca(2+) -dependent K(+) channel, which generates the charge balance for Cl(-) secretion. The non-genomic response to aldosterone in distal colon appears to enhance the capacity for absorption while down-regulating the potential for secretion. We have also demonstrated rapid (< 1 min) non-genomic activation of Na(+)-H(+) exchange, K(+) recycling, PKC alpha activity, and a PKC delta- and PKA-dependent Ca(2+) entry through di-hydropyridine-blockable Ca(2+) channels specifically by 17beta-estradiol in distal colon. These rapid effects are female gender specific and are insensitive to inhibitors of the classical estrogen receptor (ER). 17 beta-Estradiol directly stimulated the activity of both PKC delta and PKC alpha (but not PKC epsilon or PKC zeta) in a cell-free assay system. E2 rapidly inhibited basolateral K(Ca) channel activity which would be expected to result in an acute inhibition of Cl(-) secretion. Physiological concentrations of E2 (0.1-10 nM) reduced both basal and secretagogue-induced Cl(-) secretion. This anti-secretory effect of E2 is sensitive to PKC inhibition, intracellular Ca(2+) chelation, and is female gender specific and insensitive to inhibitors of the classical ER. These observations link rapid non-genomic activation of second messengers with a rapid gender-specific physiological effect in the whole tissue. Aldosterone and E2 differ in their protein kinase signal transduction and both hormones stimulate specific PKC isoforms indicating both common and divergent signalling systems for salt-retaining steroid hormones. The physiological function of non-genomic effects of aldosterone and estradiol is to shift the balance from net secretion to net absorption in a pluripotential epithelium.
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PMID:Non-genomic convergent and divergent signalling of rapid responses to aldosterone and estradiol in mammalian colon. 1196 Jun 25

The adrenal glands are a major source of steroid hormone biosynthesis. In normal physiology, the pituitary hormone corticotropin (ACTH) regulates the secretion of glucocorticoids via its G protein-coupled receptor (ACTHR), the product of the MC2R gene. Aldosterone is another major product of the adrenal gland; its regulation is controlled mainly by the renin-angiotensin system, although ACTH plays a role, too, especially under certain pathological conditions. The adrenal gland also secretes lesser amounts of androgens and intermediate metabolites of all these steroids. Unregulated secretion of any of these hormones can be caused by tumors, adrenocortical adenomas or carcinomas, and/or bilateral (or, rarely, unilateral) hyperplasia. Cortisol-producing hyperplasia of the adrenal glands is caused by two distinct syndromes, both of which have been directly or indirectly associated with protein kinase A signaling: (i) primary pigmented nodular adrenocortical disease (PPNAD) (a micronodular form of bilateral adrenal hyperplasia), either isolated (rarely) or in the context of Carney complex, is caused (in most cases) by mutations of the PRKAR1A gene; and (ii) ACTH-independent macronodular adrenal hyperplasia (AIMAH), or massive macronodular adrenal disease (MMAD), has been associated with aberrant (ectopic) expression, and presumably regulation, of various G protein-coupled receptors. AIMAH is a rare, sporadic condition affecting predominantly middle-aged men and women with an almost equal ratio (the latter in contrast to other forms of endogenous Cushing's syndrome). Some familial cases of AIMAH have also been described, and it appears that the pathophysiological phenomena underlying AIMAH may be present in the far more common, sporadic adrenocortical tumors and, perhaps, in the nodular growth detected in the adrenal glands of the elderly in the general population. Thus, the study of ectopic receptor expression and cAMP-dependent PKA activity in AIMAH may have wider implications for adrenal and, indeed, endocrine tumorigenesis.
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PMID:Cyclic AMP-dependent signaling aberrations in macronodular adrenal disease. 1211 80

The serum- and glucose-regulated kinase (SGK1) gene has recently been identified as an important aldosterone-induced protein kinase that mediates trafficking of the renal epithelial Na(+) channel (ENaC) to the cell membrane. Thus, SGK1 is an appealing candidate for blood pressure regulation and possibly essential hypertension. To test this hypothesis, we recruited monozygotic (126 pairs) and dizygotic (70 pairs) normotensive twin subjects and parents of dizygotic twins. Blood pressure was measured in a controlled fashion: recumbent, sitting, and upright. We documented genetic variance on blood pressure in all positions. We then relied on microsatellite markers at the SGK1 gene locus (D6S472, D6S1038, and D6S270) and 2 single nucleotide polymorphisms within the SGK1 gene. We found significant linkage of the SGK1 gene locus to diastolic blood pressure (P<0.0002) and suggestive evidence for linkage for systolic blood pressure (P<0.04), documenting the locus as a quantitative trait locus for blood pressure. We next performed association, using all dizygotic twins and a monozygotic member from each pair. We found significant associations between both single nucleotide polymorphism variants and blood pressure, as well as a significant interaction between the single nucleotide polymorphisms enhancing the effect. This combined effect of the polymorphisms was confirmed in an independent sample of 260 young normotensive men. We conclude that the SGK1 gene is relevant to blood pressure regulation and probably to hypertension in man.
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PMID:Serum- and glucocorticoid-regulated kinase (SGK1) gene and blood pressure. 1221 63

A non-genomic antisecretory role for dexamethasone at low concentrations (0.1 nM to1 microM) is described in monolayers of human bronchial epithelial cells in primary culture and in a continuous cell line (16HBE14o- cells). Dexamethasone produced a rapid decrease of [Ca(2+)](i) (measured with fura-2 spectrofluorescence) to a new steady-state concentration. After 15 min exposure to dexamethasone (1 nM), [Ca(2+)](i) was reduced by 32 +/- 11 nM (n = 7, P < 0.0001) from a basal value of 213 +/- 36 nM (n = 7). We have shown previously that aldosterone (1 nM) also produces a rapid fall in [Ca(2+)](i); however, after the decrease in [Ca(2+)](i) induced by dexamethasone, subsequent addition of aldosterone did not produced any further lowering of [Ca(2+)](i). The rapid response to dexamethasone was insensitive to pretreatment with cycloheximide and unaffected by the glucocorticoid type II and mineralocorticoid receptor antagonists RU486 and spironolactone, respectively. The rapid [Ca(2+)](i) decrease induced by dexamethasone was inhibited by the Ca(2+)-ATPase pump inhibitor thapsigargin (1 microM), the adenylate cyclase inhibitor MDL hydrochloride (500 microM) and the protein kinase A inhibitor Rp-adenosine 3',5'-cyclic monophosphorothioate (200 microM), but was not affected by the protein kinase C inhibitor, chelerythrine chloride (0.1 microM). Treatment of 16HBE14o- cell monolayers with dexamethasone (1 nM) inhibited the large and transient [Ca(2+)](i) increase induced by apical exposure to ATP (10(-4) M). Dexamethasone (1 nM) also reduced by 30 % the Ca(2+)-dependant Cl(-) secretion induced by apical exposure to ATP (measured as the Cl(-)-sensitive short-circuit current across monolayers mounted in Ussing chambers). Our results demonstrate, for the first time, that dexamethasone at low concentrations inhibits Cl(-) secretion in human bronchial epithelial cells. The rapid inhibition of Cl(-) secretion induced by the synthetic glucocorticoid is associated with a rapid decrease in [Ca(2+)](i) via a non-genomic mechanism that does not involve the classical glucocorticoid or mineralocorticoid receptor. Rather, it is a result of rapid non-genomic stimulation of thapsigargin-sensitive Ca(2+)-ATPase, via adenylate cyclase and protein kinase A signalling.
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PMID:Rapid non-genomic inhibition of ATP-induced Cl- secretion by dexamethasone in human bronchial epithelium. 1248 92

We have previously demonstrated that, in rat, the stimulatory effect of 5-HT on aldosterone secretion is mediated through a 5-HT7 receptor subtype. The aim of the present study was to characterize the transduction mechanisms associated with activation of native 5-HT7 receptors. 5-HT induced a dose-dependent increase in cAMP production in rat glomerulosa cells. Pretreatment of cells with the adenylyl cyclase (AC) inhibitor SQ 22536 or the protein kinase A (PKA) inhibitor H-89 markedly attenuated the effect of 5-HT on aldosterone secretion. Administration of 5-HT in the vicinity of glomerulosa cells induced a robust increase in cytosolic calcium concentration ([Ca2+]i) and this effect was abrogated by the T-type calcium channel blocker mibefradil. Patch-clamp studies confirmed that 5-HT activated a T-type calcium current. H-89 attenuated both the [Ca2+]i response and the activation of T-type calcium current induced by 5-HT. Reduction of extracellular calcium concentration in the medium or administration of mibefradil caused a marked reduction of the maximum effect (Emax) of 5-HT on aldosterone secretion. These data demonstrate that activation of native 5-HT7 receptors stimulates cAMP formation, which in turn provokes calcium influx through T-type calcium channels. Both the activation of the AC/PKA pathway and the calcium influx are involved in 5-HT-induced aldosterone secretion.
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PMID:Involvement of T-type calcium channels in the mechanism of action of 5-HT in rat glomerulosa cells: a novel signaling pathway for the 5-HT7 receptor. 1253 Jun 78

Ghrelin is an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), which has been originally isolated from rat stomach. Evidence has been previously provided that adrenal gland possesses abundant ghrelin-displaceable GHS-Rs, but nothing is known about the possible role of ghrelin in the regulation of adrenocortical function. Reverse transcription-polymerase chain reaction demonstrated the expression of ghrelin and GHS-R in the rat adrenal cortex, and high adrenal concentrations of immunoreactive ghrelin were detected by radioimmune assay (RIA). Autoradiography localized abundant [(125)I]ghrelin binding sites in the adrenal zona glomerulosa (ZG) and outer zona fasciculata (ZF). Ghrelin (from 10(-10) to 10(-8) M) did not affect either basal steroid hormone (pregnenolone, progesterone, 11-deoxycorticosterone, corticosterone, 18-hydroxycorticosterone and aldosterone) secretion from dispersed ZG and zona fasciculata/reticularis (ZF/R) cells (as evaluated by quantitative high pressure liquid chromatography), or basal and agonist-stimulated aldosterone and corticosterone production from cultured ZG and ZF/R cells, respectively (as measured by RIA). Ghrelin (10(-8) and 10(-6) M) raised basal, but not agonist-stimulated, proliferation rate of cultured ZG cells (percent of cells able to incorporate 5-bromo-2'-deoxyuridine), without affecting apoptotic deletion rate (percent of cells able to incorporate biotinylated nucleosides into apoptotic DNA fragments). The tyrosine kinase (TK) inhibitor tyrphostin-23 and the p42/p44 mitogen-activated protein kinase (MAPK) inhibitor PD-98059 abolished the proliferogenic effect of 10(-8) M ghrelin, while the protein kinase A and C inhibitors H-89 and calphostin-C were ineffective. Ghrelin (10(-8) M) stimulated TK and MAPK activity of dispersed ZG cells, and the effect was abolished by preincubation with tyrphostin-23 and PD-98059, respectively. Tyrphostin-23 annulled ghrelin-induced activation of MAPK activity. Taken together, the present findings indicate that (i) ghrelin and GHS-R are both expressed in the rat adrenal cortex, ghrelin binding sites being very abundant in the ZG; (ii) ghrelin does not affect the secretory activity of rat adrenocortical cells, but significantly enhances the proliferation rate of cultured ZG cells, without affecting apoptotic deletion rate; and (iii) the ZG proliferogenic action of ghrelin involves the TK-dependent activation of the p42/p44 MAPK cascade.
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PMID:Ghrelin and growth hormone secretagogue receptor are expressed in the rat adrenal cortex: Evidence that ghrelin stimulates the growth, but not the secretory activity of adrenal cells. 1258 59

Aldosterone increases within 30 min renal Na+reabsorption and K+secretion by a mechanism that is triggered at the level of gene transcription. Thus, gene products that are rapidly up- or down-regulated transmit this effect to the transport machinery within the distal nephron target cells. One such rapidly up-regulated gene product is a structural element of the transport machinery, namely the a subunit of ENaC. Its amount might in certain conditions play a rate limiting role for Na+transport. Cell-surface localization and function of ENaC and of the Na,K-ATPase are also tightly controlled by a complex regulatory network and aldosterone appears to acutely regulate the expression of elements of this network such as the small G-protein K-Ras (in A6 cells) and the kinase SGK1 (also in ENaC-expressing cells of the mammalian distal nephron). The kinase SGK1 is an early aldosterone-induced protein that relays signals from pathways that are transmitted via PDK1/2 and possibly PKA. Active SGK1 has been shown to increase ENaC and Na,K-ATPase cell-surface expression in Xenopus oocytes. This effect at the level of ENaC has been recently shown to be mediated by the ubiquitin ligase Nedd4-2 which is a direct target of SGK1. Once phosphorylated by SGK1, Nedd4-2 is prevented from interacting with ENaC and thus from decreasing ENaC cell-surface expression. This SGK1-Nedd4-2-ENaC pathway is the first direct link between aldosterone-induced transcriptional regulation and the function of the Na+transport machinery to be unravelled. The physiological importance of this pathway for mediating the aldosterone response in different target epithelia remains to be verified in vivo, in particular in view of the axial gradient of ENaC apical translocation observed along the aldosterone-sensitive distal nephron.
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PMID:SGK1: aldosterone-induced relay of Na+ transport regulation in distal kidney nephron cells. 1264 99

In human adrenal cells, cholesterol for steroidogenesis is derived from both high-density lipoproteins (HDL) via the Scavenger Receptor Class B Type I (SR-BI) and low-density lipoproteins (LDL) via the LDL receptor pathway. We have previously shown that, in the human adrenocortical carcinoma cell line, NCI-H295R, SR-BI and LDL receptor expression and steroidogenesis are coordinately regulated by activators of protein kinase A (PKA) leading to glucocorticoid synthesis. In the present study, we studied whether SR-BI and LDL receptor expression are regulated by activators of the protein kinase C (PKC) signaling pathway, such as angiotensin II, which stimulate mineralocorticoid synthesis. First, it is shown that, in NCI-H295R cells, aldosterone synthesis is stimulated by a phorbol ester (phorbol-12-myristate-13 acetate, PMA), a potent PKC activator. Northern blot analysis indicated that both angiotensin II and PMA stimulated SR-BI expression in a time-dependent manner. LDL receptor expression is slightly stimulated by PMA. The induction of SR-BI gene expression occurs at the transcriptional level, via an activation of the human SR-BI promoter, as shown by transient transfection experiments. Finally, SR-BI protein level was increased in angiotensin II- and PMA-stimulated cells, resulting in higher lipoprotein binding and specific cholesteryl ester (CE) uptake from HDL, as well from LDL after angiotensin II and PMA stimulation.
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PMID:Regulation of the scavenger receptor BI and the LDL receptor by activators of aldosterone production, angiotensin II and PMA, in the human NCI-H295R adrenocortical cell line. 1266 73


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