Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.11 (CD10)
 9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The current study was designed to characterize the functionally active tachykinin receptors involved in tachykinin-elicited contractions in the pig intravesical ureter, and to investigate the possible modulation exerted by the natural tachykinins substance P (SP) and neurokinin A (NKA) on the non-adrenergic non-cholinergic (NANC) excitatory ureteral neurotransmission. In pig intravesical ureteral strips pretreated with phosphoramidon (10(-5) mol/L) to block the endopeptidase activities, isometric force recordings showed that SP, NKA, and the NK2 receptor selective agonist [beta-Ala(8)]-NKA (4-10), all three induced contractions, with the following potency order: NKA > [beta-Ala(8) ]-NKA (4-10) > SP. [Sar(9), Met(O(2))(11)]-SP and senktide, selective agonists of the NK1 and NK3 receptors, respectively, failed to modify the ureteral tone. Urothelium removal and incubation with tetrodotoxin (10(-6) mol/L), phentolamine (10(-7) mol/L), propranolol (3 x 10(-6) mol/L), atropine (10(-7) mol/L) and indomethacin (3 x 10(-6) mol/L), did not alter the contraction induced by a submaximal (10(-7) mol/L) dose of [beta-Ala(8)]-NKA (4-10). MEN 10,376 (10(-8)-10(-7) mol/L), a NK2 receptor antagonist, reduced the contraction to 3 x 10(-8) mol/L NKA. GR 82334 (10(-6) -10(-5) mol/L) and SR 142801 (10(-8)-10(-7) mol/L), selective antagonists of the NK1 and NK3 receptors, respectively, did not modify that contraction. In pig intravesical ureteral strips in NANC conditions, SP and NKA induced a potentiation of the contractions to electrical field stimulation (EFS) and to exogenous ATP. The results suggest that the tachykinins evoke a direct contraction of pig intravesical ureteral strips through NK2 receptors located in the smooth muscle. SP and NKA exert an enhancement of the NANC excitatory neurotransmission of the pig intravesical ureter.
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PMID:NK2 tachykinin receptors mediate contraction of the pig intravesical ureter: tachykinin-induced enhancement of non-adrenergic non-cholinergic excitatory neurotransmission. 1138 96

When isolated mouse fat pads were incubated with insulin or sodium orthovanadate (vanadate) for up to 4h, the intracellular leptin content was increased by insulin, while it was decreased by vanadate. Bupranolol, a beta3-adrenergic receptor antagonist, prevented both effects of vanadate, i.e., the decrease in intracellular leptin and increase in cellular cAMP content, while BRL 37344, a beta3-adrenergic receptor antagonist mimicked the action of vanadate. H-89 prevented the vanadate-induced decrease in intracellular leptin, suggesting the involvement of a cAMP-dependent protein kinase (PKA). No detectable difference in the incorporation of [3H]leucine into leptin was observed between incubations of the fat pads with and without vanadate, suggesting that the action of vanadate is independent of decreasing synthesis. Similar concentrations of MG-132, a membrane-permeable proteasome inhibitor, prevented the vanadate-induced decrease in both intracellular leptin content and leptin secretion, suggesting the involvement of the proteasome in the vanadate action. The proteasome fraction separated from the vanadate-treated fat pads increased the degradation of exogenous [125I]leptin in the presence of an ATP-regenerating system together with an ubiqutination system. The endopeptidase activity against Cbz-Leu-Leu-Glu-beta-naphthylamine also was increased by the proteasome fraction. MG-132 prevented both increased effects. The 8-Br-cAMP-treated proteasome fraction increased the degradation of the exogenous leptin. H-89 prevented the effect of 8-Br-cAMP. These results indicate that vanadate decreases the intracellular leptin content by increased degradation via a cAMP/PKA-dependent process involving proteasome activation.
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PMID:Orthovanadate decreases the leptin content in isolated mouse fat pads via proteasome activation. 1236 13

Sarcolemmal ATP-sensitive potassium (KATP) channels have been mentioned to participate in preconditioning protection. Since these channels are altered in diabetes, it would be possible that preconditioning does not develop in diabetic (D) hearts. The purpose of this study was to assess whether early (EP) and late (LP) ischemic preconditioning protect diabetic hearts against stunning in a conscious diabetic sheep model and whether diabetes might have altered KATP channel functioning. Sheep received alloxan monohydrate (1 g) and were ascribed to three experimental groups: control (DC, 12 min of ischemia (I) followed by 2 h of reperfusion (R)), early preconditioning (DEP, six 5 min I-5 min R periods were performed before the 12 min I) and late preconditioning (DLP, same as DEP except that the preconditioning stimulus was performed 24 h before the 12 min I). Regional mechanics during reperfusion was evaluated as the percent recovery of wall thickening fraction (%WTH) expressed as percentage of basal values (100%) and KATP behaviour was indirectly assessed by monophasic action potential duration (MAPD) and sensitivity to glibenclamide blockade (0.1 and 0.4 mg/Kg). The results were compared to those obtained in normal (N) sheep. EP and LP protected against stunning in normal sheep (%WTH: NC = 63 +/- 3.7, NLP = 80 +/- 5**, NEP = 78 +/- 3*, *p < 0.05 and **p < 0.01 against NC) whereas contrary results occurred in diabetic ones, where DLP (%WTH = 60 +/- 4) afforded a similar recovery to DC (%WTH = 54 +/- 5) and DEP surprisingly worsened instead of improving mechanical function (%WTH = 38 +/- 6, p < 0.01 against DC). KATP channel behaviour appeared altered in diabetic hearts as shown by MAPD during ischemia in normal sheep (153 +/- 9 msec) compared to diabetic ones (128 +/- 11 msec, p < 0.05) and by the sensitivity to glibenclamide (while 0.4 mg/Kg blocked action potential shortening in normal and diabetic animals, 0.1 mg/Kg completely blocked KATP in diabetic but not in normal hearts, p < 0.05). A sarcolemmal KATP channel dysfunction might afford a primary approach to explain the absence of ischemic preconditioning protection against stunning in diabetic sheep.
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PMID:Absence of ischemic preconditioning protection in diabetic sheep hearts: role of sarcolemmal KATP channel dysfunction. 1295 94

PepN and its homologues are involved in the ATP-independent steps (downstream processing) during cytosolic protein degradation. To obtain insights into the contribution of PepN to the peptidase activity in Escherichia coli, the hydrolysis of a selection of endopeptidase and exopeptidase substrates was studied in extracts of wild-type strains and two pepN mutants, 9218 and DH5alphaDeltapepN. Hydrolysis of three of the seven endopeptidase substrates tested was reduced in both pepN mutants. Similar studies revealed that hydrolysis of 10 of 14 exopeptidase substrates studied was greatly reduced in both pepN mutants. This decreased ability to cleave these substrates is pepN-specific as there is no reduction in the ability to hydrolyse exopeptidase substrates in E. coli mutants lacking other peptidases, pepA, pepB or pepE. PepN overexpression complemented the hydrolysis of the affected exopeptidase substrates. These results suggest that PepN is responsible for the majority of aminopeptidase activity in E. coli. Further in vitro studies with purified PepN revealed a preference to cleave basic and small amino acids as aminopeptidase substrates. Kinetic characterization revealed the aminopeptidase cleavage preference of E. coli PepN to be Arg>Ala>Lys>Gly. Finally, it was shown that PepN is a negative regulator of the sodium-salicylate-induced stress in E. coli, demonstrating a physiological role for this aminoendopeptidase under some stress conditions.
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PMID:PepN is the major aminopeptidase in Escherichia coli: insights on substrate specificity and role during sodium-salicylate-induced stress. 1466 77

Epithelium of the gallbladder and biliary tract is exposed to high concentrations of potentially harmful exogenous and endogenous compounds excreted into primary bile. As the ATP-dependent efflux pump ABCG2 can prevent cellular accumulation of anticancer drugs, estrogen sulfate, xenobiotics, porphyrins, and sterols, its expression in the biliary tract might mediate protection by hindering their penetration. We therefore investigated the expression and subcellular distribution of ABCG2 in normal and malignant human gallbladder. After demonstrating ABCG2 expression in gallbladder epithelium by RT-PCR and Western blotting, we analyzed the subcellular localization of ABCG2 by indirect immunofluorescence in gallbladder adenocarcinoma specimens, and compared it to that in cholelithiasis, and normal gallbladder samples (n = 54). In control, cholelithiasis, and well-differentiated tumor samples (grade 1, T1-3), ABCG2 is present at the luminal membrane of epithelial cells, which was proven by colocalization of apical-bound TRITC-labeled lectin (wheat germ agglutinin). In poorly differentiated gallbladder adenocarcinomas, intracellular ABCG2, in addition to luminal ABCG2 immunoreactivity, was found in 13/21 carcinoma samples (grade 2 and 3, T2-4, P < 0.01). In 3/11 of grade 3 tumors, ABCG2 was present in the cytoplasmatic compartment only (P < 0.01). In proliferating bile ducts of cholangiocarcinomas, ABCG2 showed an analogous staining pattern with presence in cytosolic compartments. However, the apical marker enzyme neutral endopeptidase remained on the membrane in all samples. To study whether phosphatidylinositol 3-kinase (PI3K) signaling might be necessary for ABCG2 membrane insertion, we treated freshly isolated human gallbladder epithelial cells with the PI3K inhibitor wortmannin. As assessed by indirect immunofluorescence, this maneuver redistributes ABCG2 to intracellular compartments. In conclusion, our data suggest a protective role for ABCG2 in well-differentiated gallbladder epithelial cells. Cytoplasmatic accumulation of ABCG2 in poorly differentiated carcinomas might coincide with malfunctioning of PI3K-signaling pathways during tumor progression.
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PMID:Subcellular localization of the ABCG2 transporter in normal and malignant human gallbladder epithelium. 1514 67

The effect of different cooling temperatures and durations on resistance to freezing and to frozen storage at -20 degrees C in Lactobacillus acidophilus RD758 was studied, by using a central composite rotatable design. A cold adaptation was observed when the cells were maintained at moderate temperature (26 degrees C) for a long time (8h) before being cooled to the final temperature of 15 degrees C. These conditions led to a low rate of loss in acidification activity during frozen storage (0.64 minday(-1)) and a high residual acidification activity after 180 days of frozen storage (1011 min). The experimental design allowed us to determine optimal cooling conditions, which were established at 28 degrees C during 8h. Adaptation to cold temperatures was related to an increase in the unsaturated to saturated fatty acid ratio and in the relative cycC19:0 fatty acid concentration. Moreover, an increased synthesis of four specific proteins was observed as an adaptive response to the optimal cooling conditions. They included the stress protein ATP-dependent ClpP and two cold induced proteins: pyruvate kinase and a putative glycoprotein endopeptidase.
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PMID:Influence of cooling temperature and duration on cold adaptation of Lactobacillus acidophilus RD758. 1592 81

Expression of the structural genes encoding the ATP-dependent proteases ClpCP and Lon in Corynebacterium glutamicum and Streptomyces lividans is activated by the transcriptional regulator ClgR in response to yet unknown environmental stimuli. As it was not known whether ClgR controls expression of additional genes we used DNA microarrays in order to comprehensively define the ClgR regulon in C. glutamicum. The mRNA levels of 16 genes decreased >/= 2-fold in a DeltaclgRDeltaclpC mutant (ClgR absent) compared with a DeltaclpC mutant (ClgR present). For five genes in four operons (NCgl0748, ptrB, hflX and NCgl0240-recR) regulation by ClgR could be independently verified by primer extension analyses and confirmation of binding of purified ClgR to the regulatory regions of these operons. ptrB encodes an endopeptidase, which is consistent with the proteolytic functions of the genes already known to be under ClgR control. However, RecR is unrelated to proteolysis but required for recombinational repair of UV-induced DNA damage. Possibly ClgR-dependent activation of gene expression is triggered by environmental stresses damaging both proteins and nucleic acids, although DNA damage induced by UV radiation and mitomycin C treatment did not result in ClgR-dependent transcriptional activation of any of the newly identified ClgR regulon members. In order to functionally analyse the NCgl0748 and hflX genes we have constructed C. glutamicum strains with deletions in these genes. The DeltaNCgl0748 mutant displayed reduced growth rates in minimal and rich media. The NCgl0748 protein was shown to be localized in the cytoplasm only, while the HflX pool is equally distributed between cytoplasm and plasma membrane. In order to study the proposed degradation of ClgR by ClpCP we have constructed a conditional clpP1P2 mutant. Depletion of ClpP1 and ClpP2 in that strain resulted in the accumulation of ClgR, indicating that ClgR is in fact a substrate of the ClpCP1 and/or ClpCP2 protease in C. glutamicum.
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PMID:The transcriptional activator ClgR controls transcription of genes involved in proteolysis and DNA repair in Corynebacterium glutamicum. 1597 86

It is widely accepted that a high sodium intake triggers blood pressure rise. However, only one-third of the normotensive subjects were reported to show salt-sensitivity in their blood pressure. Many factors have been proposed as causes of salt-sensitive hypertension, but none of them provides a satisfactory explanation. We propose, on the basis of accumulated data, that the reduced activity of the kallikrein-kinin system in the kidney may provide this link. Renal kallikrein is secreted by the distal connecting tubular cells and all kallikrein-kinin system components are distributed along the collecting ducts in the distal nephron. Bradykinin generated is immediately destroyed by carboxypeptidase Y-like exopeptidase and neutral endopeptidase, both quite independent from the kininases in plasma, such as angiotensin converting enzyme. The salt-sensitivity of the blood pressure depends largely upon ethnicity and potassium intake. Interestingly, potassium and ATP-sensitive potassium (K(ATP)) channel blockers accelerate renal kallikrein secretion and suppress blood pressure rises in animal hypertension models. Measurement of urinary kallikrein may become necessary in salt-sensitive normotensive and hypertensive subjects. Furthermore, pharmaceutical development of renal kallikrein releasers, such as K(ATP) channel blockers, and renal kininase inhibitors, such as ebelactone B, may lead to the development of novel antihypertensive drugs.
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PMID:A missing link between a high salt intake and blood pressure increase. 1665 1

The ATP-dependent Clp protease has been well-characterized in Escherichia coli, but knowledge of its function in higher plants is limited. In bacteria, this two-component protease consists of a Ser-type endopeptidase ClpP, which relies on the ATP-dependent unfolding activity from an Hsp100 molecular chaperone to initiate protein degradation. In the chloroplasts of higher plants, multiple isoforms of the proteolytic subunit exist, with Arabidopsis having five ClpPs and four ClpP-like proteins termed ClpR predicted in its genome. In this work we characterized an Arabidopsis mutant impaired in one subunit of the chloroplast-localized Clp protease core, ClpR1. clpR1-1, a virescent mutant, carries a pre-mature stop codon in the clpR1 gene, resulting in no detectable ClpR1 protein. The accumulation of several chloroplast proteins, as well as most of the chloroplast-localized Clp protease subunits, is inhibited in clpR1-1. Unexpectedly, some plastid-encoded proteins do not accumulate, although their transcripts accumulate to wild-type levels. Maturation of 23S and 4.5S chloroplast ribosomal RNA (cp-rRNA) is delayed in clpR1-1, and both RNAs accumulate as higher molecular weight precursors. Also, chloroplasts in clpR1-1 are smaller than in wild type and have fewer thylakoid membranes with smaller grana stacks. We propose that a ClpR1-containing activity is required for chloroplast development and differentiation and in its absence both are delayed.
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PMID:An Arabidopsis thaliana virescent mutant reveals a role for ClpR1 in plastid development. 1700 84

Enzymes of the ATP-independent Deg serine endopeptidase family are very flexible with regard to their substrate specificity. Some family members cleave only one substrate, while others act as general proteases on unfolded substrates. The proteolytic activity of Deg proteases is regulated by PDZ protein interaction domains. Here we characterized the HhoA protease from Synechocystis sp. strain PCC 6803 in vitro using several recombinant protein constructs. The proteolytic activity of HhoA was found to increase with temperature and basic pH and was stimulated by the addition of Mg(2+) or Ca(2+). We found that the single PDZ domain of HhoA played a critical role in regulating protease activity and in the assembly of a hexameric complex. Deletion of the PDZ domain strongly reduced proteolysis of a sterically challenging resorufin-labeled casein substrate, but unlabeled beta-casein was still degraded. Reconstitution of the purified HhoA with total membrane proteins isolated from Synechocystis sp. wild-type strain PCC 6803 and a DeltahhoA mutant resulted in specific degradation of selected proteins at elevated temperatures. We concluded that a single PDZ domain of HhoA plays a critical role in defining the protease activity and oligomerization state, combining the functions that are attributed to two PDZ domains in the homologous DegP protease from Escherichia coli. Based on this first enzymatic study of a Deg protease from cyanobacteria, we propose a general role for HhoA in the quality control of extracytoplasmic proteins, including membrane proteins, in Synechocystis sp. strain PCC 6803.
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PMID:The serine protease HhoA from Synechocystis sp. strain PCC 6803: substrate specificity and formation of a hexameric complex are regulated by the PDZ domain. 1761 90


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