Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.4.4 (adenosine deaminase)
 5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of neuropeptide Y (NPY) on cell contractions of ventricular myocytes isolated from the adult rat heart was investigated. Maximum changes in cell length (dL) during stimulated (0.5 Hz) contractions were determined in presence of the phosphodiesterase inhibitor Ro 20-1724 (0.5 mM) and adenosine deaminase (5 U/ml). Under these basal conditions NPY (10(-6) M) reduced dL by 39% of control. Isoproterenol (10(-6) M) increased dL by 105% of control; the EC50 was 2 x 10(-9) M. NPY reduced the increase in dL achieved by isoproterenol in a dose dependent manner. The IC50 value was 1 x 10(-9) M and NPY (10(-6) M) produced complete inhibition. In the absence of the phosphodiesterase inhibitor the IC50 was 4 x 10(-9) M. The EC50 of isoproterenol and IC50 of NPY producing accumulation of cAMP in myocytes (Millar et al. 1988) exceeded the respective values of dL by one order of magnitude. Prior treatment of the myocytes with pertussis toxin abolished the potency of NPY to antagonize the increase in dL by isoproterenol while not interfering with the response to the beta-agonist. These results demonstrate a negative inotropic effect of NPY on the ventricular myocardial cell. Complete abolition of the effect of NPY by pertussis toxin indicate that this effect is mediated by a sarcolemmal receptor for NPY linked to adenylate cyclase via an inhibitory guanine nucleotide binding protein.
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PMID:The negative inotropic effect of neuropeptide Y on the ventricular cardiomyocyte. 255 54

The effect of neuropeptide Y (NPY) on adenylate cyclase activity was examined in ventricular myocytes isolated from the adult rat heart. In the presence of the phosphodiesterase inhibitor Ro 20-1724 (0.5 mM) and adenosine deaminase (5 U/ml), these intact cells accumulate cyclic AMP when stimulated by isoproterenol. NPY (10(-9) to 10(-6) M) reduced the degree of cAMP accumulation achieved by 10(-7) M isoproterenol in a dose dependend manner by 10 to maximally 48%. The IC50 value was 3 x 10(-8) M NPY. A maximal concentration (10(-6) M) of N6-phenylisopropyladenosine (PIA) decreased cAMP levels by 39%, i.e. to a similar extent. Prior treatment of the myocytes with pertussis toxin (1 microgram/ml for 6 h) increased the mean stimulated values in the presence of isoproterenol (10(-7) M) by a factor 4.1. In such cells, NPY and PIA were ineffective in antagonizing the stimulation of cAMP production by isoproterenol. These results indicate that the ventricular myocyte has receptors for NPY, similar to the A1 adenosine-receptor in that they are linked to the adenylate cyclase by an inhibitory guanylate binding protein.
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PMID:The antiadrenergic effect of neuropeptide Y on the ventricular cardiomyocyte. 285 10

The restriction fragment length polymorphisms (RFLPs) associated with neuropeptide Y (NPY) and somatostatin loci were used to assess the possibility of linkage to a locus for affective disorder (AD). When somatostatin haplotypes were assigned to members of 2 AD pedigrees under either rare dominant or recessive transmission, the LOD scores obtained at 0% recombination were inconsistent with linkage. Similar results were obtained with NPY under rare dominant inheritance. Comparison of the frequency of the genotypes deduced from the polymorphic alleles of gastrin-releasing peptide, NPY, somatostatin and substance P in normals vs patients with either AD or schizophrenia suggests the absence of association. The difference in the frequency of the 3.3 kb adenosine deaminase fragment in normals vs bipolar and schizophrenic patients is of borderline significance.
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PMID:Neuropeptide gene polymorphisms in affective disorder and schizophrenia. 289 62

The present study has employed immunocytochemistry on free-floating sections of adult rat medulla oblongata to characterise the distribution of nitric oxide synthase- (NOS), adenosine deaminase- (ADA) and neuropeptide Y- (NPY) immunoreactivity (IR) throughout the entire rostro-caudal axis of the nucleus tractus solitarius (NTS). In addition, unilateral nodose ganglionectomy was performed in a group of rats to determine whether any observed immunoreactivity was associated with central vagal afferent terminals. NOS-IR was found throughout the entire NTS, in cells, and both varicose and non-varicose fibres. Furthermore, unilateral nodose ganglionectomy resulted in a clear reduction in NOS-IR (visualised with diaminobenzidine) in a highly restricted portion of the ipsilateral medial NTS. Similarly, ADA- and NPY-containing cells, fibres and terminals were also found throughout the adult rat NTS. However, following unilateral nodose ganglionectomy, there was no apparent reduction in either ADA-IR or NPY-IR on the denervated side of the NTS. These data indicate a role for nitric oxide, purines and neuropeptide Y as neuromodulators within the rat NTS, although only nitric oxide appears to be primarily associated with vagal afferent input. Adenosine deaminase and neuropeptide Y-containing neurons appear to be predominantly postsynaptic to vagal input, although their possible association with vagal afferents cannot be completely excluded.
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PMID:The distribution of nitric oxide synthase-, adenosine deaminase- and neuropeptide Y-immunoreactivity through the entire rat nucleus tractus solitarius: Effect of unilateral nodose ganglionectomy. 971 Jan 47

Membrane peptidases are a group of ectoenzymes with a broad functional repertoire. In protein metabolism, their importance is well known, especially in peptide degradation and amino acid scavenging at the intestinal and renal brush border. However, they also perform more subtle tasks; not only do they provide or extinguish signals by cleaving exterior peptide mediators, but they also may function as receptors or participate in signal transduction or in adhesion. Dipeptidyl peptidase IV (DPPIV), which is identical to the lymphocyte surface glycoprotein CD26, is unique among these peptidases because of its ability to liberate Xaa-Pro and less efficiently Xaa-Ala dipeptides from the N-terminus of regulatory peptides. It occurs in the plasma membrane as a homodimer with a total molecular mass of 22-240 KdA and the C-terminal domain probably forms on alpha/beta hydrolase fold. In addition to, but independent of its serine type catalytic activity, DPPIV binds closely to the soluble extracellular enzyme adenosine deaminase. The in vivo expression on epithelial, endothelial and lymphoid cells of DPPIV is compatible with a role as physiological regulator of a number of peptides that serve as biochemical reporters between and within the immune and neuroendocrine system. Surprisingly, not cytokines with a N-terminal Xaa-Pro motif, but a number of chemokines have recently been identified as substrates. Despite DPPIV mediates only a minimal N-terminal truncation, important alterations in chemokine activities and receptor specificitIes were observed in vitro together with modified inflammatory and antiviral responses. Most probably the great flexibility of the N-terminus of a number of chemokines facilitates the accessibIlity to the catalytic site of DPPIV. Other known substrates which are subject in vitro to receptor-specific changes induced by DPPIV truncation include neuropeptides such as substance P, peptidE YY and neuropeptide Y. On the other hand, DPPIV mediated cleavage of the N-terminal His-Ala or Tyr-Ala dipeptides from circulating incretin hormones like, glucagon-like peptides (GLP)-1 and -2, gastric inhibitory polypeptide (GIP), all members of the enteroglucagon/GRF superfamily, results in their biological inactivation in vitro and in vivo. Administration of specific DPPIV inhibitors closes this pathway of incretin degradation and greatly enhances insulin secretion. The improved glucose tolerance in several animal models for type II diabetes points to specific DPPIV inhibition as a pharmaceutical approach for type 2 diabetes drug development.
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PMID:Peptide truncation by dipeptidyl peptidase IV: a new pathway for drug discovery? 1128 88

DP (dipeptidyl peptidase) IV is the archetypal member of its six-member gene family. Four members of this family, DPIV, FAP (fibroblast activation protein), DP8 and DP9, have a rare substrate specificity, hydrolysis of a prolyl bond two residues from the N-terminus. The ubiquitous DPIV glycoprotein has proved interesting in the fields of immunology, endocrinology, haematology and endothelial cell and cancer biology and DPIV has become a novel target for Type II diabetes therapy. The crystal structure shows that the soluble form of DPIV comprises two domains, an alpha/beta-hydrolase domain and an eight-blade beta-propeller domain. The propeller domain contains the ADA (adenosine deaminase) binding site, a dimerization site, antibody epitopes and two openings for substrate access to the internal active site. FAP is structurally very similar to DPIV, but FAP protein expression is largely confined to diseased and damaged tissue, notably the tissue remodelling interface in chronically injured liver. DPIV has a variety of peptide substrates, the best studied being GLP-1 (glucagon-like peptide-1), NPY (neuropeptide Y) and CXCL12. The DPIV family has roles in bone marrow mobilization. The functional interactions of DPIV and FAP with extracellular matrix confer roles for these proteins in cancer biology. DP8 and DP9 are widely distributed and indirectly implicated in immune function. The DPL (DP-like) glycoproteins that lack peptidase activity, DPL1 and DPL2, are brain-expressed potassium channel modulators. Thus the six members of the DPIV gene family exhibit diverse biological roles.
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PMID:Dipeptidyl peptidase IV and related enzymes in cell biology and liver disorders. 1558 1

Based on the importance of tuberomammillary nucleus (TMN) as a target for feeding/arousal-related functions, we aimed in the present study to investigate hypothalamic neuronal origin of neuropeptide Y (NPY) and cocaine- and amphetamine-regulated transcript (CART) fibers projecting to the histaminergic nucleus. In the first series of experiments, we examined NPY (or CART) fiber distribution within the boundary of adenosine deaminase (ADA)-immunoreactive (ir) TMN regions; extensive NPY (or CART)-ir axon terminals were observed in E4 (TMMd), E3 (TMMv), and E2 (TMVr) subdivisions. NPY varicosities co-contained vesicular GABA transporters (vGAT). CART boutons, however, contained either vGAT or vesicular glutamate transporters (vGLU), which suggested dual (or multiple) origins of CART fibers. Based on the previous observation on melanin-concentrating hormone (MCH)-ir neuronal elements in the TMN, their coexistence with CART peptide was examined in detail. In E4 subdivision, approximately 40.8% of MCH-ir somata co-contained CART, but the proportion was reduced to 24.1% in E3 region. In E2 and E1 (TMVc) regions, only MCH-ir axon terminals existed without any MCH-ir somata. In the second series of experiments, we investigated hypothalamic neuronal origin of NPY (or CART) fibers projecting to the TMN. The arcuate nucleus (Arc) was the sole source of hypothalamic NPY fibers projecting to the nucleus. In contrast, CART fibers in the TMN originated from the Arc as well as the other hypothalamic nuclei including the retrochiasmatic nucleus, paraventricular nucleus, lateral hypothalamus (LH), zona incerta (ZI), and dorsal hypothalamic area. Quantitative analysis showed that arcuate CART projection to the TMN occupied approximately 23.5% of the total hypothalamic CART input to the nucleus, while the rest originated mainly from the LH and ZI. The present observations suggested that the TMN might play a key role in energy balance and arousal, by receiving periphery-derived, first-order NPY (or CART) inputs from the Arc as well as second-order (and downstream) CART inputs from the other hypothalamic nuclei.
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PMID:Hypothalamic neuronal origin of neuropeptide Y (NPY) or cocaine- and amphetamine-regulated transcript (CART) fibers projecting to the tuberomammillary nucleus of the rat. 2792 37