Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both alpha-1 and alpha-2 adrenoceptors have been localized to the renal cortex, with the majority of binding sites on the proximal tubule. Because the major regulator of Na+ uptake into the proximal tubule is the Na+/H+ exchanger, and because alpha-1 and alpha-2 adrenoceptors stimulate it in other tissues, we tested the hypothesis that both alpha adrenoceptor subtypes can increase Na+ uptake into the proximal nephron by stimulating the Na+/H+ antiporter. Enhancement of Na+ transport by agonists was studied in isolated rat proximal tubules by determining the uptake of 22Na that was suppressible by the Na+/H+ inhibitor, 5-(N-ethyl-N-isopropyl)amiloride (EIPA). The phorbol ester, phorbol-12-myristate-13-acetate, (0.1 microM), directly stimulated the antiporter through protein kinase C and increased EIPA-suppressible 22Na uptake 250% above control. The alpha-1 adrenoceptor agonists, cirazoline and phenylephrine, in addition to the mixed agonist, norepinephrine, maximally stimulated uptake by 226 to 232% at 1 microM concentrations. alpha-2 agonists produced a range of maximal stimulations at 1 microM from 65% with guanabenz to 251% with B-HT 933. Increases in 22Na uptake by agonists were inhibited by selective adrenergic antagonists and by EIPA. The drugs did not change the EIPA-resistant component of 22Na uptake. Inasmuch as the adrenoceptor subtypes likely stimulated Na+/H+ exchange by differing intracellular pathways impinging upon common transport steps, we examined whether simultaneous stimulation of both pathways was additive. Submaximal concentrations (5 nM each) of alpha-1 and alpha-2 adrenoceptor agonists in combination synergistically enhanced 22Na uptake to a level similar to 1 microM concentrations of adrenoceptor agonists alone or in combination.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Synergistic alpha-1 and alpha-2 adrenergic stimulation of rat proximal nephron Na+/H+ exchange. 256 49

Dopamine, like other neurotransmitters, exerts its biological effects by occupation of specific receptor subtypes. The dopamine receptors in the central nervous system and certain endocrine organs are classified into the D1/D2 subtypes. Outside the central nervous system, the dopamine receptors are classified into the DA1/DA2 subtypes. The D1/D2 and DA1/DA2 receptor have marked similarities and some differences, the most notable of which is the lower affinity of the DA dopamine compared with the D dopamine receptor. DA1 receptor activation increases renal blood flow (RBF); stimulation of DA1 and DA2 receptors may also increase glomerular filtration rate (GFR). DA1 agonists inhibit fluid and electrolyte transport indirectly via hemodynamic mechanisms and directly by occupation of DA1 receptors in specific nephron segments. In the proximal tubule, DA1 agonists simulate adenylate cyclase and inhibit Na+-H+ antiport activity. They also increase phospholipase C and inhibit Na+-K+-ATPase activity (presumably as a consequence of protein kinase C activation). The latter effects may be facilitated by DA2 agonists. In cortical collecting ducts, dopamine antagonizes the effects of mineralocorticoids and the hydrosomotic effect of antidiuretic hormone. It has also been suggested that DA1 may also decrease sodium transport by influencing other hormones, such as atrial natriuretic peptide. Studies of dopamine in the young are complicated because of the propensity for dopamine to stimulate alpha-adrenoceptors. Dopamine alone may actually decrease RBF in the perinatal period. In some animals, the renal vasodilatory and natriuretic effects of dopamine increase with age. Renal tubular DA1-stimulated adenylate cyclase activity increases, whereas renal tubular DA1 receptors decrease with age. Renal DA2 receptor density is greater in the fetus; after birth renal DA2 receptors do not change. Endogenous dopamine may regulate sodium excretion in the young differently than in the adult. In the adult, sodium surfeit is associated with an increase in urinary dopamine; the opposite occurs in the young. A decrease in dopamine production or blockade of dopamine receptors results in an antinatriuresis in the adult; dopamine blockade in the young results in a natriuresis. It remains to be determined whether these age-related differences in dopamine effects are due to changes in receptor DA subtype density, second messengers, and/or interaction with other receptors.
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PMID:The dopamine receptor in adult and maturing kidney. 257 2

The long-term renal epithelial cell line LLC-PK1 expresses at confluence several differentiated characteristics of renal proximal tubule including Na/glucose cotransport and several brush border membrane hydrolases. The differentiation-inducing chemical hexamethylene bisacetamide (HMBA) triggers a dramatic induction of Na+/glucose symport, trehalase and maltase, expressed as an increase in the number of cells in the culture that express the differentiated phenotype. Characteristics of the induction response are reviewed in terms of proposed mechanisms of inducer action. New evidence suggests that in addition to elevation of intracellular Na levels mediated by partial inhibition of the sodium pump, HMBA treatment also alters polyamine levels via effects on ornithine decarboxylase. These responses may be mediated by HMBA effects on protein kinase C activity. The possible role of polyamine fluctuations and DNA demethylation in mediating HMBA effects on differentiated gene expression is currently being investigated.
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PMID:Chemical inducers of differentiation in a long-term renal cell line. 264 78

Gluconeogenesis is a major metabolic function of the renal proximal tubular cell. To characterize the regulation of this process in proximal tubule, glucose production from gluconeogenic precursors was measured in proximal tubular segments prepared from dog kidney. Production of glucose was a linear function of time for up to 120 min of incubation at 37 degrees C under a variety of conditions. Lowering the pH of incubation media from 7.5 to 7.0 increased glucose synthesis. Production of glucose was inhibited by 3-mercaptopicolinate. Incubation of proximal tubular segments with insulin diminished synthesis of glucose. Incubation of segments with tumor-promoting phorbol esters, 12-O-tetradecanoylphorbol-13-acetate or phorbol 12,13-dibutyrate, resulted in decreased production of glucose. This effect was not observed following incubation with the inactive phorbol ester 4 alpha-phorbol. Changes in glucose synthesis could not be attributed to alterations in cell viability or in rates of glucose oxidation induced by experimental maneuvers. Our findings confirm the usefulness of proximal tubular segments for characterization of metabolic processes in this portion of the nephron. The experimental results are consistent with a role for protein kinase C in the control of gluconeogenesis in proximal tubule.
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PMID:Phorbol esters inhibit gluconeogenesis in canine renal proximal tubular segments. 392 47

Cells respond to increase in volume by activating solute efflux pathways, resulting in water loss and restoration of the original cell volume. The solute efflux pathways underlying these volume regulatory decrease (VRD) responses have been relatively well studied. However, the transduction pathways whereby the change in cell volume is converted into an intracellular signal resulting in VRD are much less well understood. We have examined VRD in isolated proximal tubule cells from the frog, with particular attention to the roles of stretch-activated channels, Ca2+ and protein kinases. Cell length was taken as an index of cell volume, and was measured continuously using a photodiode array. VRD was observed in approximately 50% of cells, and was inhibited by Ba2+, Gd3+ and 4,4'-diisothiocyanatostilbene 2,2'-disulphonic acid (DIDS), and removal of extracellular Ca2+. VRD was accelerated by the active phorbol ester, phorbol 12-myristate 13-acetate (PMA), and the phosphatase inhibitor F-; on the other hand, VRD was prolonged by 4 alpha-phorbol 12,13-didecanoate (PDC), an inactive phorbol ester), and inhibited by PMA and Gd3+, PMA and 0 Ca2+, and staurosporine. Volume regulation was unaffected by di-butyryl cAMP and 3-isobutyl-1-methyl-xanthene (IBMX). These data suggest that Ca2+ and PKC, via protein phosphorylation, play a stimulatory role in VRD.
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PMID:Volume regulatory responses in frog isolated proximal cells. 752 37

Opossum kidney OKP cells express an apical membrane Na+/H+ antiporter that is encoded by NHE-3 (for Na+/H+ exchanger 3) and is similar in many respects to the renal proximal tubule apical membrane Na+/H+ antiporter. Chronic incubation of OKP cells in acid medium for 24 hr increases Na+/H(+)-antiporter activity and NHE-3 mRNA abundance. The increase in Na+/H(+)-antiporter activity was not prevented by H7, a protein kinase C/protein kinase A inhibitor, but was prevented by herbimycin A, a tyrosine kinase inhibitor. Incubation of cells in acid medium increased c-src activity, and this was inhibited by herbimycin A. To determine the role of the src family of nonreceptor protein-tyrosine kinases, Csk (for carboxyl-terminal src kinase), a physiologic inhibitor of these kinases, was overexpressed in OKP cells. In three clones overexpressing csk, acid-induced increases in Na+/H(+)-antiporter activity and NHE-3 mRNA abundance were inhibited. In these clones, inhibition of acid activation of Na+/H(+)-antiporter activity paralleled inhibition of acid activation of c-src. Neither herbimycin A nor overexpression of csk inhibited dexamethasone-induced increases in Na+/H(+)-antiporter activity. These studies show that decreases in pH activate c-src and that the src family nonreceptor protein-tyrosine kinases play a key role in acid activation of NHE-3.
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PMID:Overexpression of csk inhibits acid-induced activation of NHE-3. 754 36

Purinergic P2 receptors are present on proximal renal tubules, but their function is unknown. Because P2 agonists antagonize vasopressin-stimulated water transport in the distal tubule by inhibiting activation of adenylyl cyclase, we postulated that P2 receptor activation blocks parathyroid hormone (PTH) inhibition of phosphate uptake in proximal tubule by preventing PTH-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) generation. PTH inhibition of sodium-dependent phosphate uptake was attenuated by alpha,beta-methylene-ATP (AMP-CPP), a P2x receptor agonist, but not by 2-methyl-thio-ATP, a P2y receptor agonist, in a dose-dependent manner. AMP-CPP did not attenuate inhibition of phosphate uptake produced by direct activation of adenylyl cyclase with forskolin, by addition of the cAMP analogue 8-bromo-cAMP, or by inhibition of cAMP phosphodiesterase with RO-20-1724. Additionally, AMP-CPP had no effect on basal or PTH-stimulated cAMP production. As PTH also stimulates protein kinase C activation, the effect of AMP-CPP on inhibition of phosphate uptake stimulated by phorbol 12-myristate 13-acetate (PMA) was tested. AMP-CPP had no effect on PMA-induced inhibition of phosphate uptake. Pretreatment with pertussis toxin abolished the attenuating effect of AMP-CPP on PTH inhibition of sodium-dependent phosphate uptake. We conclude that activation of purinergic P2 receptors attenuates the inhibitory effect of PTH on sodium-dependent phosphate uptake by a G protein-dependent mechanism that is independent of cAMP generation protein kinase A activation, or protein kinase C activation.
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PMID:P2 purinoceptor stimulation attenuates PTH inhibition of phosphate uptake by a G protein-dependent mechanism. 757 78

We recently cloned a partial cDNA (35H) for a protein kinase C (PKC) binding protein from a rat kidney cDNA library and demonstrated that it is a PKC substrate in vitro (Chapline, C., Ramsay, K., Klauck, T., and Jaken, S. (1993) J. Biol. Chem. 268, 6858-6861). Additional library screening and 5' rapid amplification of cDNA ends were used to obtain the complete open reading frame. Amino acid sequence analysis, DNA sequence analysis, and Northern analysis indicate that 35H is a unique cDNA related to alpha-and beta-adducins. Antisera prepared to the 35H bacterial fusion protein recognized two polypeptides of 80 and 90 kDa on immunoblots of kidney homogenates and cultured renal proximal tubule epithelial cell extracts. The 35H-related proteins were similar to alpha- and beta-adducins in that they were preferentially recovered in the Triton X-100-insoluble (cytoskeletal, CSK) fraction of cell extracts and were predominantly localized to cell borders. Phorbol esters stimulated phosphorylation of CSK 35H proteins, thus emphasizing that sequences isolated according to PKC binding activity in vitro are also PKC substrates in vivo. The phosphorylated forms of the 35H proteins were preferentially recovered in the soluble fraction, thus demonstrating that phosphorylation regulates their CSK association and, thereby, their function in regulating cytoskeletal assemblies. We have isolated another PKC binding protein partial cDNA (clone 45) from a rat fibroblast library with substantial homology to alpha-adducin. Antisera raised against this expressed sequence recognized a protein of 120 kDa, the reported size of alpha-adducin, on immunoblots of renal proximal tubule epithelial cell extracts. A 120-kDa protein that cross-reacts with the clone 45 (alpha-adducin) antisera coprecipitated with 35H immunecomplexes, indicating that alpha-adducin associates with 35H proteins in vivo. Taken together, these results indicate that 35H is a new, widely expressed form of adducin capable of forming heterodimers with alpha-adducin. We propose naming this adducin homologue gamma-adducin.
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PMID:35H, a sequence isolated as a protein kinase C binding protein, is a novel member of the adducin family. 759 23

Renal tubular reabsorption of phosphate is critical to the maintenance of phosphate homeostasis in mammals, and the brush-border membrane Na-P(i) cotransport systems in proximal tubules play a major role in this process. We have isolated a cDNA encoding a mouse sodium-dependent phosphate transport protein (Npt1), which is expressed primarily in the kidney. This protein is highly similar to its human and rabbit homologues, based on nucleotide and amino acid comparisons. The presence of potential Asn-linked glycosylation and protein kinase C phosphorylation sites that are conserved among all three homologues suggests that these sites may be important in the function and regulation of this protein. The Npt1 gene was mapped to mouse chromosome 13, close to the Tcrg locus. By both in situ hybridization and reverse transcription-polymerase chain reaction, Npt1 mRNA was localized predominantly to the proximal tubule.
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PMID:Cloning, genetic mapping, and expression analysis of a mouse renal sodium-dependent phosphate cotransporter. 761 45

Although it is suggested that in the renal proximal tubules, dopamine D1 receptor activation causes inhibition of Na+/K+ATPase via a phospholipase C and protein kinase C coupled pathway, the direct stimulation of protein kinase C by dopamine has not been reported. The present study was designed to examine the effects of dopamine and selective dopamine D1 receptor and dopamine D2 receptor agonists on protein kinase C activity. The renal proximal tubule suspensions were obtained from male Sprague-Dawley rats. The tubules were incubated separately with dopamine and fenoldopam in the presence or absence of dopamine D1 receptor antagonist, SCH 23390 ([(R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine]). The protein kinase C activity was measured by using a kinase target peptide, conjugated to a fluorescent molecule in water. The amino acid sequence of this peptide is, Proline-Leucine-Serine-Arginine-Threonine-Leucine-Serine-Valine-Alanine- Alanine-Lysine(PKSRTLSVAAK). We found that dopamine and fenoldopam [6-chloro-2,3,4,5-tetrahydro-1-(4-hydroxyphenyl)-1H-3-benzazepine-7,8-di ol] produced concentration-dependent increases in protein kinase C activity, which was blocked by SCH 23390. However, the dopamine D2 receptor agonist, bromocriptine [(5' alpha)-2-bromo-12'-hydroxy-2'-(1-methyl-ethyl)-5'-(2-methylpropyl)erg o- taman-3',6',18-trione] failed to stimulate protein kinase C activity at all the concentrations tested. These results provide direct evidence that dopamine stimulates protein kinase C activity via activation of dopamine D1 receptors.
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PMID:Dopamine causes stimulation of protein kinase C in rat renal proximal tubules by activating dopamine D1 receptors. 762 15


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