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)

Neutral endopeptidase (NEP; CALLA, CD10, EC 3.4.24.11) is a cell surface endopeptidase that hydrolyses bioactive peptides, including the bombesin-like peptides, as well as other neuropeptides. Bombesin-like peptides and other neuropeptides are autocrine growth factors for both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Low expression of NEP has been reported in SCLC and NSCLC cell lines. NEP inhibition has been shown to increase proliferation in one cell line. To date, NEP expression has not been quantitatively evaluated in normal adult lung, SCLC or NSCLC tumors, paired uninvolved lung from the same patient, or in other pulmonary neoplasms such as mesotheliomas and carcinoids. We examined the expression of NEP in these tissues and human cell lines using immunohistochemistry, flow cytometry, enzyme activity, ELISA, Western blot, and reverse transcription (RT)-PCR. Uninvolved lung tissue from different individuals displayed considerable variation in NEP activity and protein. By immunohistochemistry, NEP expression was detectable in alveolar and airway epithelium, fibroblasts of normal lung, and in mesotheliomas, whereas it was undetectable in most SCLC, adenocarcinoma, squamous cell carcinoma, and carcinoid tumors of the lung. NEP activity and protein levels were lower in all SCLC and adenocarcinoma tumors when compared to adjacent uninvolved lung, often at levels consistent with expression derived from contaminating stroma. NEP expression and activity were reduced or undetectable in most SCLC and lung adenocarcinoma cell lines. NEP mRNA by RT-PCR was not expressed or was in low abundance in the majority of lung cancer cell lines. The majority of lung tumors did not express NEP by RT-PCR as compared with normal adjacent lung. In addition, recombinant NEP abolished, whereas an NEP inhibitor potentiated, the calcium flux generated by neuropeptides in some lung cancer cell lines, demonstrating potential physiological significance for low NEP expression. NEP, therefore, is a signal transduction and possibly a growth modulator for both SCLC and NSCLC, emphasizing the role of neuropeptides in the pathogenesis of the major histological forms of lung cancer.
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PMID:Neutral endopeptidase: variable expression in human lung, inactivation in lung cancer, and modulation of peptide-induced calcium flux. 863 Oct 21

By the simultaneous measurement of acetylcholine release and smooth muscle contraction in rabbit tracheal segments with and without epithelium, pre- as well as postsynaptic effects of this cell layer were studied on cholinergic neurotransmission. The epithelial cell layer exerted a presynaptic inhibitory influence on acetylcholine release, induced by KCl and electrical stimulation, with a concomitant decrease in the smooth muscle contractions. The responses elicited by exogenous acetylcholine, acting postsynaptically, were also inhibited in the presence of the epithelium. The epithelial effect was not accounted for by the production of inhibitory prostaglandins or a nitric oxide-synthase product. Furthermore, the epithelium did not function as a metabolic site for the degradation of acetylcholine. Phosphoramidon, an inhibitor of neutral endopeptidase, mimicked the effects of epithelium removal on the cholinergic responses to high frequency stimulation and on the acetylcholine-induced effects. Neutral endopeptidase inhibition did not further enhance the responses in epithelium-denuded segments. We therefore suggest that the inhibitory function of the epithelium can be partly explained by the activity of neutral endopeptidase, limiting the excitatory effects of tachykinins on cholinergic responses. An alteration in the neutral endopeptidase activity as a result of inflammatory responses and epithelial damage can contribute to the mechanism of airway hyperreactivity in asthma.
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PMID:Epithelial modulation of cholinergic responses in rabbit trachea is partly due to neutral endopeptidase activity. 872 Apr 81

Neutral endopeptidase (EC 3.4.24.11; NEP), originally isolated from renal tubular brush border, is a cell surface peptidase identical to the CD10 antigen (or CALLA; common acute lymphoblastic leukemia antigen) in lymphoid cells. We studied the serum NEP levels daily after transplantation (Tx) in 19 renal allograft recipients. The NEP activity was determined with a two-step enzymatic assay utilizing a fluorogenic substrate (Suc-Ala-Ala-Phe-AMC; see text) and related to clinical signs of graft rejection, to signs of immunoactivation in transplant fine-needle aspiration biopsy (FNAB) specimens, to renal function, and to serum levels of C-reactive protein. The serum NEP levels remained normal (peak level 10.3 +/- 1.8 micrograms/l on days 6-9 after Tx, initial level after Tx 7.3 +/- 1.4 micrograms/1 on day 2; mean values +/- SEM) in patients who neither showed clinical signs of rejection nor had findings of immunoactivation in FNAB samples. On the contrary, the serum NEP levels rose clearly in patients developing acute rejection verified clinically and in FNAB samples (peak value 90.4 +/- 18.7 micrograms/l on days 6-9 post-Tx; p < 0.001 compared with patients without sings of immunoactivation) and even in patients having immunoactivation in FNAB without clinical evidence of rejection (108.2 +/- 22.4 micrograms/l, p < 0.001). Serum NEP peak appeared 2-3 days before clinical diagnosis of rejection and a positive findings in FNAB samples. Serum NEP increments did not correlate with changes in serum creatinine, delayed onset of renal excretory function, blood leukocyte count, C-reactive protein level, or infections. Thus, the serum NEP activity was shown to increase after renal allotransplantation associated with early phases of immunoactivation and development of acute graft rejection. Because of the limited number of patients studied, the clinical implications of these preliminary observations for kidney transplant monitoring clearly need confirmation in larger studies.
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PMID:Increased serum neutral endopeptidase activity in acute renal allograft rejection. 873 78

1. Neutral endopeptidase (NEP) EC 3.4.24.11 is a zinc-metallopeptidase which is partly responsible for the degradation of atrial natriuretic peptide (ANP) in vivo. 2. ANP inhibits vascular smooth muscle cell proliferation, and elicits vasorelaxation of the systemic and, more potently, the pulmonary vasculature. Plasma ANP levels are elevated in human disease states characterized by pulmonary hypertension, and in animal models of these diseases. 3. However, the short in vivo half-life of ANP suggests that it has limited therapeutic potential. Therefore, it has been hypothesized that inhibition of the metabolism of ANP may prove successful in the treatment of pulmonary hypertension. 4. Several inhibitors of NEP have been shown to reduce the development of pulmonary hypertension secondary to chronic hypoxia in rats. In addition, the inhibitor SCH 42495, partially reversed the established cardio-pulmonary remodelling associated with this disease model, without elevating plasma ANP levels. 5. The physiological actions of ANP are many of the properties desirable in a treatment for pulmonary hypertension. Thus, attenuating the metabolism of this peptide using NEP inhibitors, should potentially enhance the effects of ANP, either by maintaining plasma levels or at a local, tissue level.
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PMID:Neutral endopeptidase inhibitors and the pulmonary circulation. 885 87

The spatial location of neutral endopeptidase 24.11 (NEP) immunoreactivity was compared to that of substance P (SP), SP receptor (NK-1r) and identified gastric efferent neurons in the dorsal vagal complex in rat brainstem. The majority of NEP labeling was observed caudal to the obex. Neutral endopeptidase-immunoreactivity was associated with the central canal, ependyma and blood vessels, and surrounded the area postrema. A comparison of the results of immunocytochemical and retrograde tracing experiments demonstrated the absence of co-labeling of neurons or their process with NEP and either substance P or NK-1r. Furthermore, no NEP-immunoreactivity was observed in the vicinity of identified gastric efferents in the dorsal motor nucleus of the vagus. These results would suggest that NEP does not degrade SP in the vicinity of gastric efferent neurons.
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PMID:Comparison of the spatial distribution of endopeptidase-24.11 with substance P, substance P receptor (NK-1r) and gastric efferent neurons in the dorsal vagal complex of the rat. 912 18

Mammalian cell-surface peptidases participate in the postsecretory processing and metabolism of neuropeptides and peptide hormones. Neutral endopeptidase-24.11 (NEP) is the prototype of a family of zinc metallopeptidases that also includes the endothelin-converting enzymes (ECE) and which are structurally related to the bacterial enzymes thermolysin and lactococcal endopeptidase. Two other mammalian gene products exhibit strong homology with NEP: the erythrocyte cell-surface antigen, KELL; and the putative product of the PEX gene, which has been associated with X-linked hypophosphatemic rickets. No enzymic activity has yet been attributed to KELL and PEX proteins, and they remain peptidases in search of a substrate. A wide range of biologically active peptide substrates has been described for NEP, of which the enkephalins and the atrial natriuretic peptide family have assumed greatest significance. Endothelin-converting enzyme catalyses the final step in the biosynthesis of the vasoconstrictor peptide, endothelin (ET). Like NEP, it is a type II integral membrane protein, but is expressed predominantly in endothelial cells. Isoforms of ECE (ECE-1alpha, ECE-1beta, and ECE-2) exist that differ in a number of characteristics. In particular, ECE-1, through the paracrine effects of ET-1, may contribute to the proliferation of smooth muscle after angioplasty and to the development of human atherosclerosis. Inhibitors of ECE and NEP may have important therapeutic applications in cardiovascular and renal medicine.
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PMID:Mammalian membrane metallopeptidases: NEP, ECE, KELL, and PEX. 914 2

Neutral endopeptidase (NEP, E.C. 3.4.24.11), a widely distributed ectoenzyme, cleaves and inactivates a variety of biologically active peptides, including the tachykinin, substance P (SP). This study was undertaken to determine whether the modulation of SP airway smooth muscle contraction by NEP is age-dependent. We studied the contractile response of isolated tracheal rings from newborn and 120 day old New Zealand white rabbits. We measured NEP activity and determined immunoreactive NEP content in tracheal membrane preparations. NEP activity was then localized histochemically in sections of rabbit tracheas. In the presence of the NEP inhibitor, SCH 32615, the contractile response of isolated tracheal rings to SP was increased both in the newborn and 120 day old rabbits. However, the increase was greatest in the newborn animals. NEP activity in tracheal membrane preparations increased fivefold between the newborn and 120 day old rabbits. Western blot analysis also revealed a significant increase in the immunoreactive NEP content of these tracheal membrane preparations between the newborn and 120 day old rabbits. NEP activity, localized histochemically, was most intense in the epithelial region of the newborn animals, with a shift of activity to the subepithelial region with age. The prominent epithelial localization of neutral endopeptidase in the tracheas of these 1 day old rabbits, which we have shown to have relatively low neutral endopeptidase activity, suggests that the location of neutral endopeptidase in the airway, including proximity to relevant substance P receptors, may be critical to its function.
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PMID:Neutral endopeptidase activity in newborn and adult rabbit tracheas. 927 29

Neutral endopeptidase EC 3.4.24.11 (NEP) is localized in peptidergic neurons and various colocalized peptides or other humoral mediators may serve as substrates. Target disruption of the NEP gene was reported to enhance the lethal response to endotoxin shock in mice. We examined thermonociceptive thresholds and enkephalin (ENK) tissue levels in transgenic NEP (-/-) and control wild type NEP (+/+) mice. Hot plate (52 degrees C) latency was 13.1 +/- 1.4 s in NEP (+/+) mice (n = 16) while latency increased significantly (P = 0.031) to 17.7 +/- 1.6 s in NEP (-/-) mice. Naloxone (10 mg/kg) had no effect on hot plate latency in NEP (+/+) mice (12.5 s, n = 8), but significantly decreased the latency in NEP (-/-) mice compared to untreated NEP (-/-) deficient mice (10.5 s, n = 8). Morphine (3 or 10 mg/kg) analgesic response was similar in knockout mice and wild type mice. Methionine-ENK (MET-ENK) and leucine-ENK (LEU-ENK) levels were determined in extracts from cortex, brain stem, hypothalamus, striatum, spinal cord, trigeminal ganglion and heart in treated and untreated mice. ENK-levels varied in a regionally-dependent manner and were significantly decreased in hypothalamus and spinal cord. We conclude that deletion of the NEP gene results in an opioid-related increase in thermonociceptive threshold. Regional differences in opioid metabolism indicate that NEP evokes tissue-specific patterns of ENK-regulation. NEP selectively controls opioid biosynthesis in hypothalamus and spinal cord presumably by feedback regulation.
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PMID:Opioid-related changes in nociceptive threshold and in tissue levels of enkephalins after target disruption of the gene for neutral endopeptidase (EC 3.4.24.11) in mice. 934 38

Neutral endopeptidase-24.11 (NEP; neprilysin; EC 3.4.24.11) and endothelin-converting enzyme (ECE) are related zinc metallopeptidases involved in the processing of biologically active peptides. Only ECE, however, exists as a disulphide-linked homodimer. The covalent linkage in rat ECE is between Cys412 in each subunit, which is equivalent to Glu403 in rabbit NEP. Here we report that directed mutagenesis of Glu403 to cysteine in rabbit NEP creates a disulphide-linked homodimer, as revealed by transient transfection in COS-1 cells and SDS/PAGE of a membrane fraction. Under reducing conditions, both the mutant (E403C) and the wild-type NEP migrate as a polypeptide of 92 kDa. However, under non-reducing conditions, the Mr of the wild type remains unchanged, whereas that of the mutant is doubled. Co-transfection of wild-type ECE and E403C NEP cDNA did not result in the production of a NEP-ECE heterodimer. Comparison of the kinetic constants for wild-type and E403C mutant NEP with either [D-Ala2,Leu5]enkephalin or 3-carb oxypropanoyl-alanyl-alanyl- leucine-4-nitroanilide(Suc-Ala-Ala-Leu-NH-Np) as substrate show a decrease of approx. 50% in Vmax/Km for the mutant form. The IC50 value for inhibition of the mutant by phosphoramidon or thiorphan is increased 3-fold and 5-fold respectively. Although NEP and ECE exhibit only about 40% identity and differ substantially in substrate specificity and some other characteristics, these data indicate that they have considerable similarity in three-dimensional structure, allowing dimer formation in the mutant NEP with the disulphide link probably occurring in a hydrophilic surface loop.
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PMID:Mutagenesis of Glu403 to Cys in rabbit neutral endopeptidase-24.11 (neprilysin) creates a disulphide-linked homodimer: analogy with endothelin-converting enzyme. 958 75

We characterized neutral endopeptidase activity and protein in the three aortic layers and in corresponding cultured primary cells. Neutral endopeptidase was expressed in all three layers of rat aorta with higher protein level and activity in the adventitia than in the media and intimal endothelium. Neutral endopeptidase was also found in primary cultured fibroblasts, smooth muscle and endothelial cells derived from the corresponding layers. Neutral endopeptidase activity and protein were higher in the fibroblasts and smooth muscle cells than in endothelial cells. Neutral endopeptidase inhibition prevented atrial natriuretic peptide (ANP) degradation in endothelial and smooth muscle cells. It potentiated ANP-stimulated cyclic GMP production in these cells. Neutral endopeptidase inhibition also reduced bradykinin degradation and potentiated bradykinin-stimulated release of arachidonic acid in fibroblasts and endothelial cells. Our data demonstrate the presence and functional activity of neutral endopeptidase in all three cell layers of rat aorta as well as in primary cells of the vessel. The data suggest that local concentrations of vasoactive peptides in the vessel wall might be regulated by the neutral endopeptidase cleavage pathway in the immediate vicinity of their target cells.
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PMID:Characterization of neutral endopeptidase in vascular cells, modulation of vasoactive peptide levels. 959 33


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