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

Recent studies revealed that angiotensin II (Ang II) interacts with two pharmacologically different subtypes of cell surface receptors. Type I Ang II (AT1) receptor is characterized by signal transduction mediated through G protein and phospholipase C. In this study, the micro-localization of mRNAs coding for AT1 receptor and angiotensinogen was carried out in the rat kidney, using an assay of reverse transcription and polymerase chain reaction (RT-PCR) in individual microdissected renal tubule segments along the nephron, glomeruli, vasa recta bundle, and arcuate arteries. Large signals for AT1 receptor were detected in the glomerulus, proximal convoluted tubule (PCT), proximal straight tubule (PST), cortical collecting duct, and vascular system. Small signals were also seen in medullary thick ascending limb, outer medullary collecting duct, and inner medullary collecting duct (IMCD). Angiotensinogen mRNA is expressed largely in PCT, PST, and a small amount in glomerulus and vasa recta. Our data demonstrate that Ang II could be produced locally in proximal tubule and vasa recta bundle, and that the AT1 receptor was widely distributed not only in the glomerulus and vessels but also in tubules from PCT to IMCD.
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PMID:PCR localization of angiotensin II receptor and angiotensinogen mRNAs in rat kidney. 831 39

The presence of a Na(+)-Ca2+ exchange system has been previously demonstrated at the basolateral side of the cortical collecting system. The role of such an exchanger in maintaining low intracellular [Ca2+] ([Ca2+]i) in this nephron segment is now investigated. Cells from the connecting tubule and cortical collecting duct of rabbit kidneys were isolated by immunodissection with mAb R2G9 and subsequently cultured on glass coverslips. [Ca2+]i was measured in single cells using quantitative fluorescence microscopy. Surprisingly, isoosmotic substitution of extracellular Na+ ([Na+]o) for N-methylglucamine generated [Ca2+]i oscillations in individual cells instead of an anticipated sustained increase in [Ca2+]i. The amplitude of these oscillations ranged between 150 to 600 nM (average 308 +/- 19 nM) and occurred at a frequency of 0.63 +/- 0.03 min-1, with a duration of 44 +/- 2 seconds per spike. Oscillations were only observed in response to [Na+]o less than 5 mM and lasted until Na+o was re-introduced. The compound U73122 (10 microM), a new phospholipase C inhibitor, inhibited [Ca2+]i oscillations, which strongly suggests that IP3 generation initiates [Ca2+]i oscillations. [Ca2+]i oscillations were independent of extracellular Ca2+ and could not be inhibited by lanthanum ions, indicative for an intracellular source for the generation of Ca2+ spikes. Addition of thapsigargin, a specific inhibitor of endoplasmic reticulum Ca(2+)-ATPase activity, induced a considerable intracellular Ca2+ release, after which [Ca2+]i oscillations could no longer be provoked. Caffeine (20 mM) reversibly inhibited the Ca2+ oscillations, which implies that Ca(2+)-induced Ca2+ release is involved in generating these oscillations.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ca2+ oscillations in the rabbit renal cortical collecting system induced by Na+ free solutions. 847 19

In vitro studies on single microdissected segments have been extensively used during the 20 past years to localize V1 and V2 vasopressin receptors within the mammalian kidney, and define their role in the control of water balance. Based on vasopressin-dependent adenylate cyclase activity measurements and quantitative RT-PCR studies, it is now clear that V2 receptors are present along the whole collecting duct from cortex to papilla, and, in most species, in the ascending limb of Henle's loop (thick and thin limb); occasionally in the distal tubule but not in the other segments. The stimulation by cyclic AMP of sodium chloride reabsorption in the thick ascending limb, and of urea reabsorption in the papillary collecting duct indicates that vasopressin--in addition to its well known hydroosmotic effect--also participates in the building up of the corticopapillary gradient of osmotic pressure. As regards the V1a receptor, binding studies as well as quantitative RT-PCR, and measurements of free cytosolic calcium concentration allow us to draw the following conclusions. In the rat, the V1a receptor is absent from the glomerulus, the proximal tubule (convoluted and straight portions), the tick ascending limb of Henle's loop and the terminal portion of the papillary collecting duct. It is present in the thin ascending limb and the cortical and outer medullary portions of the collecting duct. Its presence in the thin descending limb has not, up to now, been explored. By contrast with previous data in the rabbit, the V1a receptor does not alter vasopressin-dependent sodium and water reabsorption in the rat cortical collecting duct. Further studies will be necessary to determine its functional role in that segment, as well as in the thin ascending limb. Finally, vasopressin V2 agonists have been shown to induce intracellular calcium release in the papillary collecting duct, a segment devoid of V1a receptors. This effect--which cannot be ascribed to a cross-reaction with oxytocic receptors--indicates either an unusual coupling of the V2 receptor to phospholipase C or, else, the presence of a new vasopressin receptor.
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PMID:[Functional expression of vasopressin receptors V1a and V2 along the mammalian nephron]. 859 Feb 15

Previously, we demonstrated that a mouse inner medullary collecting duct cell line (mIMCD-K2) secretes Cl- by an electrogenic mechanism via cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channels [N. L. Kizer, B. Lewis, and B. A. Stanton. Am. J. Physiol. 268 (Renal Fluid Electrolyte Physiol. 37): F347-F355, 1995; N. L. Kizer, D. Vandorpe, B. Lewis, B. Bunting, J. Russell, and B. A. Stanton. Am. J. Physiol. 268 (Renal Fluid Electrolyte Physiol. 37): F854-F861, 1995; D. Vandorpe, N. Kizer, F. Ciampolillo-Bates, B. Moyer, K. Karlson, W. B. Guggino, and B. A. Stanton. Am. J. Physiol. 269 (Cell Physiol. 38): C683-C689, 1995]. The objective of the present study was to determine whether adenosine, and adenosine A1 receptors (A1AR) specifically, regulate electrogenic Cl- secretion (IscCl) in mIMCD-K2 cells. Neither N6-cyclohexyladenosine (CHA), a specific A1AR agonist, nor 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a specific A1AR antagonist, altered basal, unstimulated IscCl in monolayers of mIMCD-K2 cells mounted in Ussing-type chambers. In contrast, DPCPX increased arginine vasopressin (AVP)-stimulated IscCl, an effect that was reversed by CHA. Adenosine deaminase (ADA), which oxidatively deaminates adenosine to inosine, increased AVP-stimulated IscCl. CHA reversed the stimulatory effect of ADA on AVP-stimulated IscCl. These results suggest that adenosine, via A1AR, inhibits AVP-stimulated IscCl. To identify the source(s) of extracellular adenosine, we examined the effects of dipyridamole, an inhibitor of nucleoside transport, and alpha,beta-methyleneadenosine 5'-diphosphate (AOPCP), an inhibitor of ecto-5'-nucleotidase, on AVP-stimulated IscCl. Both compounds increased AVP-stimulated IscCl. CHA reversed the stimulatory effect of dipyridamole and AOPCP on IscCl. Neither ADA nor CHA had an effect on 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (CPT-cAMP)-stimulated IscCl. Moreover, U-73122, an inhibitor of phospholipase C, failed to attenuate the increase in AVP-stimulated IscCl elicited by dipyridamole and AOPCP or the decrease in AVP-stimulated IscCl elicited by CHA. We conclude that adenosine, released by a nucleoside transporter and formed extracellularly by the breakdown of AMP, binds to A1AR, and decreases AVP-stimulated IscCl in mIMCD-K2 cells by reducing intracellular cAMP levels.
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PMID:Adenosine inhibits arginine vasopressin-stimulated chloride secretion in a mouse IMCD cell line (mIMCD-K2). 859 84

In rat inner medullary collecting duct (IMCD) cells in primary culture, hypotonic stress induces Ca2+ transients consisting of an early peak phase caused by a Ca2+ release from intracellular stores and a subsequent plateau phase that involves Ca2+ entry from the extracellular milieu. In the present study, the mechanisms by which cell swelling is transduced into the Ca2+ release were investigated. The free intracellular Ca2+ concentration ([Ca2+]i) was measured using the fluorescent dye fura-2 and cell volume using a confocal laser scanning microscope. In control experiments, after reduction of extracellular osmolarity from 600 to 300 mosmol/l, by omission of sucrose, [Ca2+]i rapidly increased from 106 +/- 9 nmol/l to a peak value of 405 +/- 22 nmol/l (P </= 0.05) and thereafter reached a steady-state of 230 +/- 23 nmol/l. In low-Ca2+ conditions (10 nmol/l), the reduction of osmolarity evoked only a transient increase of [Ca2+]i by 182 +/- 11 nmol/l (P </= 0.05), which reflected Ca2+ release from intracellular stores. Hyposmotic stress had no effect on inositol 1,4,5-triphosphate (IP3) production measured by a [3H]IP3 radioreceptor assay. Preincubation with 100 micromol/l ETYA (a non-metabolisible derivative of arachidonic acid) reduced the Ca2+ response to hyposmotic stress under high and low Ca2+ conditions (87 and 85% inhibition respectively) as well as the regulatory volume decrease (RVD). Extracellular application of arachidonic acid in isotonic medium led to an increase in [Ca2+]i under high and low Ca2+ conditions. Pretreatment of IMCD cells with 50 microg/ml D609 (a phosphatidylcholine-directed phospholipase C inhibitor) or with 200 micromol/l propranolol (a phosphatidate phosphohydrolase inhibitor) reduced the hypotonic Ca2+ response more strongly than pretreatment with 5 micromol/l BPhB (a phospholipase A2 inhibitor). The Ca2+ response was also suppressed after preincubation with 200 micromol/l RHC 80267 (a diacylglycerol lipase inhibitor). Preincubation with 50 ng/ml pertussis toxin (a G-protein inhibitor) reduced the transient component of the Ca2+ response partially. We conclude that G-proteins, phosphatidylcholine-directed phospholipase C, phospholipase A2, diacylglycerol lipase and arachidonic acid, but not IP3, are involved in the mechanisms by which Ca2+ is released from the intracellular stores during RVD in IMCD cells.
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PMID:Arachidonic acid as a second messenger for hypotonicity-induced calcium transients in rat IMCD cells. 906 39

The effect of extracellular calcium ([Ca2+]e) on cytosolic calcium ([Ca2+]i) was investigated in thick ascending limbs and collecting ducts from the rat kidney, using the fluorescent dye fura-2. In cortical collecting ducts, basolateral but not apical changes in [Ca2+]e were associated with parallel changes in [Ca2+]i. Basal [Ca2+]i was hardly modified by nifedipine and verapamil but was decreased by 60% by basolateral La3+. Increasing peritubular [Ca2+]e triggered Ca2+ release from intracellular stores. This effect was not reproduced by agonists of the renal Ca2+-receptor RaKCaR, e.g., Ba2+, Mg2+, Gd3+, and neomycin, but was reproduced by Ni2+. Ni2+-induced mobilization of intracellular Ca2+ was larger in the inner medullary collecting duct, a segment which poorly responds to increasing [Ca2+]e. In the cortical thick ascending limb, removing basolateral Ca2+ hardly altered [Ca2+]i but increasing [Ca2+]e or adding Ba2+, Mg2+, Gd3+ and neomycin released intracellular calcium. These data demonstrate that (1) basolateral influx of calcium occurs in cortical collecting ducts, under basal conditions; (2) this influx occurs through nonvoltage gated channels, permeable to Ba2+, insensitive to verapamil and nifedipine, and blocked by La3+; (3) increasing [Ca2+]e stimulates the influx and triggers intracellular calcium release, independently of the phospholipase C-coupled receptor RaKCaR; (4) RaKCaR is functionally expressed in thick ascending limbs; (5) another membrane receptor, sensitive to Ni2+ but not to Ca2+ is present in the collecting duct.
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PMID:Relationship between extra- and intracellular calcium in distal segments of the renal tubule. Role of the Ca2+ receptor RaKCaR. 907 43

The present study was undertaken to determine whether extracellular adenosine 5'-triphosphate (ATP) promotes cellular proliferation of cultured rat renal inner medullary collecting duct cells. Extracellular ATP increased inositol 1,4,5-triphosphate (IP3) production and cellular free calcium concentration - [Ca2+]i - in a dose-dependent manner. ATP also caused a transient cellular acidification. Extracellular ATP activated mitogen-activated protein (MAP) kinase and [3H]thymidine incorporation in a dose-dependent manner. However, such effects were not obtained with adenosine 5'-diphosphate, adenosine monophosphate, and adenosine. In addition, uridine triphosphate, a P(2u) purinergic agonist, increased IP3 production and activated MAP kinase. 2-Methylthio ATP, a P(2y) purinergic agonist, also increased IP3 production, but did not affect the MAP kinase activity. We also examined the effect of arginine vasopressin on cellular growth. Arginine vasopressin did not alter MAP kinase activity and [3H]thymidine incorporation in cultured rat renal inner medullary collecting duct cells. These results indicate that extracellular ATP activates phospholipase C mediated through P(2u) and P(2y) purinergic receptors and promotes cellular proliferation mediated through P(2u) purinergic receptors in renal inner medullary collecting duct cells.
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PMID:Extracellular ATP promotes cellular growth of renal inner medullary collecting duct cells mediated via P2u receptors. 920 Apr 13

The nonapeptide bradykinin (BK) plays an important role in the production of eicosanoids within the collecting duct of the nephron. We have shown previously that BK can initiate a complex signaling cascade that causes the release of arachidonic acid (AA) from MDCK-D1 cells, a canine cell line of distal tubule and collecting duct origin. This release is dependent upon early activation of specific upstream enzymes, including phosphatidylcholine-specific phospholipase C (PC-PLC) and phospholipase D (PLD). Ultimately, the release of this precursor of eicosanoids is effected by recruitment of the cytoplasmic 85-kDa form of phospholipase A2 (cPLA2). This enzyme is thought to translocate from the cytosol to cellular membranes following stimulation by agonists that cause elevations of intracellular calcium ([Ca2+]i). The present study was undertaken to examine the dependence of AA release upon Ca2+ influx in BK-stimulated MDCK cells. For this purpose, cells were incubated with 1 microM BK for 1 min and lysed in Ca(2+)-free Tris buffer. The high-speed 100000 x g pellet was extracted with 10 mM octyl glucoside and the cPLA2 protein level was determined. Previous results from our laboratory indicated that BK induced a 1.81-fold increase in cPLA2 activity associated with cellular membranes, while in the present study, Western blotting with a specific cPLA2 antibody demonstrated a similar elevation in protein detected with these same membranes. A selective inhibitor of receptor-mediated Ca2+ entry, SK&F 96365, was used to resolve the role of extracellular Ca2+ in BK's ability to evoke AA release. Pretreatment of cells with SK&F 96365 resulted in an inhibition of greater than 60% of the BK response. Taken together, these results strongly suggest that BK-mediated AA release in MDCK-D1 cells is at least partly contingent upon translocation of cPLA2 to membranes initiated by an influx of extracellular Ca2+.
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PMID:Bradykinin-induced translocation of cytoplasmic phospholipase A2 in MDCK cells. 927 29

Bradykinin (BK) plays a key role in collecting duct functions. Using an established line of principal cells of the rabbit collecting duct (R.C. SV3), we examined the characteristics of the BK receptors in these cells. [3H]-BK bound specifically to R.C. SV3. Saturation binding analyses allowed KD (968 +/- 232 pM) and Bmax values (356 +/- 43 fmol/mg protein) to be calculated. Competitive displacement of [3H]-BK was observed with Hoe-140, a specific type 2 BK receptor (BKR-2) antagonist, but not with des arg9-BK, a BKR-1 agonist. The presence of BKR-2 was confirmed by the reverse-transcription polymerase chain reaction technique. BK stimulated cytosolic calcium and inositol phosphate formation in a dose-dependent manner (from 1 nM to 1 microM). BK also inhibited the arginine vasopressin dependent increase of cyclic adenosine monophosphate. This effect could not be related to the production of prostaglandin E2. These results demonstrate the presence of high-affinity BKR-2 in the principal cells of the rabbit collecting duct that are linked to phospholipase C activity and are involved in arginine vasopressin related regulatory loops.
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PMID:Characterization of B2-bradykinin receptors in rabbit principal cells of the collecting duct. 980 25

We have used the patch-clamp technique to study the effects of changing extracellular ATP concentration on the activity of the small-conductance potassium channel (SK) on the apical membrane of the mouse cortical collecting duct. In cell-attached patches, the channel conductance and kinetics were similar to its rat homologue. Addition of ATP to the bathing solution of split-open single cortical collecting ducts inhibited SK activity. The inhibition of the channel by ATP was reversible, concentration dependent (K(i) = 64 microM), and could be completely prevented by pretreatment with suramin, a specific purinergic receptor (P(2)) blocker. Ranking of the inhibitory potency of several nucleotides showed strong inhibition by ATP, UTP, and ATP-gamma-S, whereas alpha, beta-Me ATP, and 2-Mes ATP failed to affect channel activity. This nucleotide sensitivity is consistent with P(2)Y(2) purinergic receptors mediating the inhibition of SK by ATP. Single channel analysis further demonstrated that the inhibitory effects of ATP could be elicited through activation of apical receptors. Moreover, the observation that fluoride mimicked the inhibitory action of ATP suggests the activation of G proteins during purinergic receptor stimulation. Channel inhibition by ATP was not affected by blocking phospholipase C and protein kinase C. However, whereas cAMP prevented channel blocking by ATP, blocking protein kinase A failed to abolish the inhibitory effects of ATP. The reduction of K channel activity by ATP could be prevented by okadaic acid, an inhibitor of protein phosphatases, and KT5823, an agent that blocks protein kinase G. Moreover, the effect of ATP was mimicked by cGMP and blocked by L-NAME (N(G)-nitro-l-arginine methyl ester). We conclude that the inhibitory effect of ATP on the apical K channel is mediated by stimulation of P(2)Y(2) receptors and results from increasing dephosphorylation by enhancing PKG-sensitive phosphatase activity.
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PMID:Extracellular ATP inhibits the small-conductance K channel on the apical membrane of the cortical collecting duct from mouse kidney. 1091 72


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