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)

The current understanding of the cellular mode of action of PTH has undergone deep changes during the last decade and the major acquisitions can be summarized as follows. First, results from biochemical and cell biology studies suggest the existence of at least two receptor types coupled to two distinct intracellular signaling pathways by G proteins: the phospholipase C-calcium-protein kinase C pathway would be coupled to high-affinity receptors, whereas the adenylate cyclase-cAMP-protein kinase A pathway would be coupled to low-affinity receptors. Until now, only one type of PTH receptor has been identified at the molecular level. It is very likely that additional PTH receptor types will be evidenced. Second, both PTH receptor-coupled transduction pathways are involved in the inhibitory effect of the hormone on the activity of two transport systems of the apical membrane of proximal tubular cells: Na-Pi cotransport and Na-H exchanger. These effects are the cellular basis for PTH inhibition of Pi and bicarbonate reabsorption. Which proteins are the targets of the different protein kinases remains to be established. Concerning the other effects of PTH on the proximal tubule (stimulation of neoglucogenesis and of calcitriol synthesis, and Na, K-ATPase inhibition), protein kinase C seems to play a major role. Third, in Henle's loop, PTH stimulates reabsorption of divalent cations through a dual effect under the dependence of protein kinase A, i.e., enhanced epithelial potential difference and opening of paracellular pathway. Finally, stimulation of distal calcium reabsorption results from multiple events: membrane insertion of apical calcium channels, opening of basolateral chloride channels resulting in cellular hyperpolarization, and modulation of Ca-ATPase. Again, while it is commonly acknowledged that both transduction systems are involved, their precise molecular targets remain to be identified (Table 1). The elucidation of the cellular mode of action of PTH, some examples of which have been reviewed, holds major interest far beyond the field of cell or organ physiology. It is the basis for understanding and, ultimately, for comprehensive treatment of genetic diseases characterized by functional abnormalities of molecules involved in the cascade of events leading to the effect of PTH on its cellular targets (hormone receptors, G proteins, and kinases). The second perspective is pharmacologic: molecular and structural identification of PTH-receptor interactions will be a prelude to design and synthesis of new selective, nonpeptidic hormonal analogs and antagonists that are easier to handle. The high incidence and severity of secondary hyperparathyroidism during chronic renal failure highlights the importance of this research.
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PMID:Cellular mode of action of parathyroid hormone. 815 58

Endothelin (ET), a powerful vasoconstrictive peptide, is distributed ubiquitously in various organs, including the vascular endothelium and tubules of the kidney. Although localized more abundantly to the glomerulus and inner medullary collecting duct, ET receptors have been identified in the proximal tubule. The possible effects of ET on proximal tubule transport and the potential role of second messengers in this process have not been described fully. To define the role of ET in proximal tubule transport, renal cortical slices were incubated for 3 min in the presence of various concentrations of ET. Incubation with low concentrations of ET-1 (1 x 10(-9) to 1 x 10(-11) M) within the physiological range stimulated both Na(+)-Pi cotransport and Na+/H+ exchange. Pretreatment with staurosporine (0.6 microM) for 25 min abolished completely the ET-induced effects on Na(+)-Pi cotransport and Na+/H+ exchange. Similarly, preincubation with phorbol ester 12-O-tetradecanoylphorbol-13-acetate (200 nM) also abolished the effects of ET on these transporters. Incubation with ET decreased significantly intracellular adenosine 3',5'-cyclic monophosphate (cAMP). Intravenous administration of pertussis toxin for 2 days prevented the ET-induced decrease in cAMP and abolished the stimulatory effects of ET on Na(+)-Pi cotransport and Na+/H+ exchange. These findings provide indirect evidence that ET participates in the regulation of proximal tubular Pi and bicarbonate homeostasis. These effects of ET are mediated by activation of protein kinase C and cAMP-dependent protein kinase A.
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PMID:Effects of endothelin on rat renal proximal tubule Na(+)-Pi cotransport and Na+/H+ exchange. 818

Intestinal calcium absorption declines with aging as a result of decreased renal 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] biosynthesis. At least part of the decline in 1,25-(OH)2D3 may be due to acquired resistance to parathyroid hormone (PTH) stimulation of renal 25-hydroxyvitamin D1-hydroxylase (1-OHase) activity. To test whether aging rats can increase 1,25-(OH)2D3 production in response to PTH, male rats of the same litter were fed a normal Ca diet and were sacrificed at 175-225 g (young rats) or 3 months later at 350-425 g (aging rats). At sacrifice, basal serum 1,25-(OH)2D3 levels (88 +/- 16 versus 49 +/- 8 pg/ml, P < 0.05) and in vitro renal proximal tubule 1-OHase activity (178 +/- 15 versus 77 +/- 5 pmol/mg protein/5 minutes, n = 6, P < 0.001) were lower in aging animals. rPTH-(1-34) (10(-11) or 10(-7) M) increased in vitro 1,25-(OH)2D3 secretion by perifused renal proximal tubules from young but not aging rats. For young and aging rats, rPTH-(1-34) (10(-7) M) increased proximal tubule cAMP-dependent protein kinase (PKA) activity, and lower concentrations (10(-11) M) stimulated translocation of protein kinase C (PKC) activity from cytosolic to soluble membrane proximal tubule cell fractions. The results of this study show that PTH activation of 1,25-(OH)2D3 production may involve both signaling pathways, with the PKC pathway responsive to lower concentrations of the hormone. The acquired resistance to PTH stimulation of 1,25-(OH)2D3 production in aging appears not to involve the hormonal activation of PKA or PKC.
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PMID:Loss of parathyroid hormone-stimulated 1,25-dihydroxyvitamin D3 production in aging does not involve protein kinase A or C pathways. 819 27

Na+/H+ exchanger isoform and the effect of high osmolality on its function was studied in cultured renal epithelial cells (LLC-PK1 and OK). Using NHE-3-specific antibody, immunoblots of luminal membranes from LLC-PK1 and OK cells specifically labeled proteins with molecular masses 90 and 95 kDa, indicating that NHE-3 is the isoform expressed on the luminal membranes of these epithelia. Proximal tubular suspensions from rabbit kidney cortex were incubated in control (310 mosm/liter) or high osmolality (510 mosm/liter) medium for 45 min and utilized for brush border membrane vesicle preparation. Influx of amiloride-sensitive 22Na+ at 10 s (pHo 7.5, pHi 6.0) into brush border membrane vesicles was 37% lower in the high osmolality group (p < 0.03). LLC-PK1 or OK cells were grown to confluence and examined for Na+/H+ exchange activity. An increase in medium osmolality to 510 mosm following acid loading decreased the 5-min uptake of the amiloride-sensitive 22Na+ in LLC-PK1 and OK cells (p < 0.04 and < 0.03 for LLC-PK1 cell OK cells, respectively). An increase in medium osmolality to 510 mosm in vascular smooth muscle cells, which express NHE-1, produced 45 and 64% stimulation of the amiloride-sensitive 22Na+ influx at base-line pHi and acid-loaded condition, respectively (p < 0.03 and < 0.01). Down-regulation of protein kinase C by preincubation with phorbol 12-myristate 13-acetate or inhibition of Ca(2+)-calmodulin-dependent protein kinase (calmodulin-kinase II) by N-6-aminohexyl-5-chloro-1-naphthalenesulfonamide (W-7) in LLC-PK1 cells did not block the inhibitory effect of high osmolality on Na+/H+ exchange activity. We conclude that renal proximal tubule epithelial cells express Na+/H+ exchange isoform NHE-3 on their luminal membranes and that hyperosmolality decreases transporter activity during cell acidification. This inhibitory effect might be unique to the NHE-3 isoform, since vascular smooth muscle cells which express NHE-1 exhibit an increase in Na+/H+ exchange activity in response to high osmolality.
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PMID:Effect of high osmolality on Na+/H+ exchange in renal proximal tubule cells. 819 9

Changes in tubular reabsorption of amino acids and other solutes are characteristic of the immature renal tubule and of various hereditary nephropathies. The cellular mechanisms governing these aberrations in renal amino acid transport have not been established. Calcium (Ca2+)-dependent protein kinases are known to phosphorylate membrane-bound carrier proteins, thereby modulating transport of various solutes by the proximal tubule. The role of these enzymes in regulating renal tubular amino acid transport, particularly during kidney development, is unknown. We investigated: (1) the effect of Ca(2+)- and phospholipid-dependent protein kinase [protein kinase C (PKC)] and Ca2+/calmodulin-dependent protein kinase II (CaMKII) on sodium chloride (NaCl)-linked proline transport by renal brush border membrane vesicles (BBMV) from adult rats using the "hypoosmotic shock" technique (lysis of vesicles); (2) the activity, expression and subcellular distribution (cytosol, particulate, BBM) of Ca(2+)-dependent protein kinases in kidneys from 7-day-old and adult rats using MBP 4-14 and autocamtide II phosphorylation assays for PKC and CaMKII, respectively, endogenous protein phosphorylation (using gel electrophoresis and autoradiography) and Western immunoblot analysis to detect PKC and CaMKII. The studies showed: (1) endogenous (membrane-bound) CaMKII and PKC as well as exogenous, highly purified PKC inhibit proline uptake by phosphorylated, lyzed/resealed BBMV when compared with control vesicles; the voltage-clamped, nonelectrogenic component of proline transport was inhibited by PKC- but not CaMKII-mediated phosphorylation; (2) a Ca(2+)-dependent activity of both kinases was evident in all subcellular fractions tested in immature and adult kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of protein phosphorylation in renal amino acid transport. 825 36

PTH stimulates synthesis and secretion of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] in renal proximal tubule cells through activation of the protein kinase-A (PKA) or the protein kinase-C (PKC) signaling pathway. The relative contribution of the two transducing systems was explored using PTH fragments with selective activation of either PKA or PKC. Rat renal proximal tubules were isolated by Percoll centrifugation, and PKA and PKC activities were measured after treatment with synthetic fragments and analogs of PTH. Rat PTH-(1-34), [Nle8,Nle15,Tyr34]bovine PTH-(3-34), and human PTH-(13-34) increased PKC activity in a dose-dependent manner. All fragments tested stimulated PKC at physiological concentrations (10(-11)-10(-10) M). Rat PTH-(1-34) (10(-7) M) increased PKA activity 4.5-fold, but other fragments failed to stimulate PKA between 10(-12)-10(-6) M. Human PTH-(28-34) stimulation of PKC was variable from experiment to experiment. All four PTH fragments tested increased 1,25-(OH)2D3 secretion by perifused renal proximal tubules at the lowest concentrations that stimulated PKC activity. The adenylate cyclase inhibitor 2',5'-dideoxyadenosine (10(-4) M) reduced PTH-(1-34)-stimulated PKA activity by 60%, but failed to block the rise in 1,25-(OH)2D3 secretion. The results of these studies demonstrate that PTH fragments that contain the PKC translocating domain stimulate 1,25-(OH)2D3 secretion, whereas elimination of the PKA activation domain does not alter the potency of the analogs' 1,25-(OH)2D3-stimulating activity. These results support the concept that PKC translocation may be required for PTH stimulation of 1,25-(OH)2D3 secretion.
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PMID:Structure-function requirements of parathyroid hormone for stimulation of 1,25-dihydroxyvitamin D3 production by rat renal proximal tubules. 834 10

This review focuses on studies from our laboratory investigating the mechanisms of chronic regulation of the Na/H antiporter in renal and nonrenal cells. Tissue culture provides an ideal tool for investigating this problem because it avoids many complicating effects that would occur in an intact animal during a chronic study. Chronic decreases in extracellular fluid pH cause an increase in Na/H antiporter activity that is dependent on protein synthesis and associated with an increase in NHE-1 (isoform of the sodium-hydrogen antiporter) mRNA abundance. This effect is associated with acid-induced increases in a number of immediate early genes, including c-fos, c-jun, junB, and egr-1. In primary cultures of rabbit proximal tubule cells, activation of protein kinase C for 2 hours causes an increase in Na/H antiporter activity that persists 24 hours later, is dependent on transcription and translation, and is associated with an increase in NHE-1 mRNA abundance. Chronic activation of protein kinase A in opossum kidney (OKP) cells causes an increase in Na/H antiporter activity that persists 16 to 20 hours later and is dependent on protein synthesis. This latter effect is of particular interest because it is opposite in direction to the acute inhibitory effect of protein kinase A on the Na/H antiporter in these cells.
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PMID:Chronic regulation of the Na/H antiporter. 839 72

PTH stimulates calcium absorption by renal distal convoluted tubules. The PTH receptor is capable of coupling to adenylyl cyclase and phospholipase C. However, it is not known whether the actions of PTH require activation of both pathways. Three approaches were taken to identify the signaling pathways responsible for stimulating calcium entry in distal convoluted tubule cells: second messengers formed in response to PTH were identified, the effects on calcium uptake of inhibiting protein kinase A (PKA) or protein kinase C (PKC) with chemical or peptide blockers were determined, and calcium transport was reconstituted by the addition of exogenous second messengers. PTH increased cAMP formation in primary cultures of mouse distal and proximal tubule cells. However, PTH stimulated inositol trisphosphate formation only in proximal tubule cells. Blocking PKA with Rp-cAMPS or the cAMP-dependent protein kinase inhibitor inhibited PTH-stimulated Ca uptake. Likewise, the PKC inhibitors, calphostin C and PKC pseudosubstrate, inhibited PTH-induced calcium uptake. Addition of forskolin (30 nM) or phorbol 12-myristate 13-acetate (10 nM) alone had no effect on Ca uptake. However, when added in combination, Ca uptake was stimulated to nearly the same extent as with concentrations of PTH that maximally stimulate calcium transport. We conclude that stimulation of calcium uptake by distal convoluted tubule cells requires activation of both PKA and PKC.
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PMID:Parathyroid hormone stimulation of calcium transport is mediated by dual signaling mechanisms involving protein kinase A and protein kinase C. 853 4

We have cloned a novel member of the CLC chloride channel family from rat brain, rCLC-5. The cDNA predicts a 83-kDa protein belonging to the branch including CLC-3 and CLC-4, with which it shares approximately 80% identity. Expression of rCLC-5 in Xenopus oocytes elicits novel anion currents. They are strongly outwardly rectifying and have a conductivity sequence of NO3- > Cl- > Br- > I- >> glutamate-. Although CLC-5 has consensus sites for phosphorylation by protein kinase A, raising the intracellular cAMP concentration had no effect on these currents. Currents were also unchanged when rCLC-5 was coexpressed with rCLC-3 and rCLC-4, either singly or in combination. rCLC-5 is expressed predominantly in kidney and also in brain, lung, and liver. Along the nephron, rCLC-5 message is detectable in all tubule segments investigated, but expression in the glomerulus and the S2 segment of the proximal tubule is low.
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PMID:Cloning and functional expression of rat CLC-5, a chloride channel related to kidney disease. 853 81

Angiotensin II (Ang II) is a potent regulator of proximal tubule functions, including transport, metabolism, and cell proliferation. The opossum kidney (OK) cell line is a useful model of renal proximal tubule. Mitogen-activated protein (MAP) kinases are rapidly phosphorylated and activated in response to various agonists. We investigated Ang II effects on serine/threonine kinase cascades in OK cells. The major findings of the present study are that Ang II stimulated MAP kinase kinase (MAPKK), MAP kinase (MAPK), and S6 kinase activities, and that it increased phosphorylation of Raf-1 kinase and p42 MAP kinase in OK cells. These stimulations of kinases were dose-dependent (from 10(-6) to 10(-11) M). The time course of activation was sequential; the peak stimulation was reached at 5 to 10 minutes for Raf-1 kinase, MAPKK and MAPK, and at 20 minutes for S6 kinase. The activation of MAPK was inhibited by approximately 70% with prolonged 24-hour PMA pretreatment or in the presence of calphostin C or H-7. Tyrosine kinase inhibitors (genistein and herbimycin) did not inhibit AngII-induced MAPK activity. This activation of MAPK was also inhibited via AT1 receptor antagonist, Dup753 and pertussis toxin. This evidence suggests that the activation of serine/threonine cascades by Ang II is largely dependent on PMA-sensitive PKC, and is not dependent on tyrosine kinase and pertussis toxin.
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PMID:Sequential activation of MAP kinase cascade by angiotensin II in opossum kidney cells. 858 39


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