Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study set out to identify the neurotransmitters involved in autonomic vasodilatation of the guinea pig uterine artery. Non-noradrenergic, paracervical neurons supplying this artery contain at least four neuropeptides: vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), dynorphin A (1-17) and somatostatin, probably in addition to acetylcholine. Transmural nerve stimulation of arterial segments precontracted with phenylephrine (3 x 10(-7) mol l-1 and treated with guanethidine (10(-6) mol l-1), produced relaxations which varied in form with the frequency of stimulation and the length of the pulse train. The relaxations were monophasic at low frequencies (< 2 Hz), and were biphasic at higher frequencies (> 5 Hz) and with longer pulse trains (> 50 pulses). Neither phase of the relaxations was reduced by hyoscine (10(-6) mol l-1), or by removal of the endothelium. The faster phase of the relaxations was selectively reduced (by 61%) during treatment with L-nitro-arginine methyl ester (L-NAME; up to 3 x 10(-5) mol l-1). This reduction was reversed by an excess of L-arginine, indicating that the fast relaxation was mediated by nitric oxide, possibly acting as a neurotransmitter. The slower phase of the neurogenic relaxation was preferentially reduced (by 43%) by the endopeptidase, trypsin (1-3 micrograms.ml-1). As VIP is the only currently identified peptide present in the paracervical neurons which causes vasodilatation, it is likely that VIP, or a closely-related peptide, is the transmitter responsible for the slow relaxation. Acetylcholine and an opioid peptide also seem to be released from the vasodilator neurons, but their effects were small, and may have been restricted to pre-synaptic sites. The slower neurogenic relaxations were inhibited by exogenous neuropeptide Y (68% reduction in amplitude), and were slightly potentiated by somatostatin (21% increase in amplitude). Therefore, endogenous stores of these peptides may also contribute to the sum effect of stimulating the paracervical vasodilator neurons. In conclusion, many different substances may act as autonomic co-transmitters from these pelvic vasodilator neurons.
 ...
PMID:Co-transmission from autonomic vasodilator neurons supplying the guinea pig uterine artery. 809 24

Recent evidence supports the hypothesis of a direct action of LHRH at the level of the prostate. Since peptidases able to degrade the hormone are present in several LHRH target structures, it was deemed of interest to investigate whether the prostate of adult normal male rats might possess LHRH degrading activities (LHRH-DA). Through the use of RP-HPLC, it has been observed that LHRH-DA is present in the soluble fraction of the rat ventral prostate homogenate, and is able to hydrolyze synthetic LHRH and to generate fragments 1-3 and 1-5 of the decapeptide. The degradation of [pGlu-3H]LHRH is inhibited by LHRH itself, and affected by several LHRH agonists and antagonists with different kinetics and potencies. TRH, the enkephalin analog [D-Ala2-D-Leu5]enkephalin and rat prolactin do not inhibit the degradation of [pGlu-3H]LHRH by the soluble fraction of prostate homogenate; on the contrary, this is inhibited by graded doses of somatostatin. The prostatic LHRH-DA is also inhibited, in a dose dependent manner, by bacitracin, serine protease inhibitors (diisopropylfluorophosphate and phenylmethansulfonylfluoride), the metal chelating agent EDTA, HgCl2, and dithiothreitol. No inhibitory effect on [pGlu-3H]LHRH hydrolysis was observed after incubation of the prostatic extract in the presence of captopril. The prostatic LHRH-DA seems to be different from that present in other tissues of the rat (e.g., hypothalamus, pituitary, gonads), and to be decreased by castration performed 3 weeks before. These results suggest that (1) an LHRH-DA is found in the soluble fraction of rat prostate homogenate; (2) this enzymatic activity exhibits the characteristics of a metallo- and thiol-dependent neutral endopeptidase; (3) it appears to be different from similar hydrolytic activities found in other tissues; and (4) it is influenced by the hormonal milieu, since castration causes a significant decrease of its activity.
 ...
PMID:Characterization of a soluble LHRH-degrading activity in the rat ventral prostate. 825 44

A metalloendopeptidase that selectively cleaves doublets of basic amino acids on the amino-terminal side of arginine residues was purified to homogeneity from rat testes and analyzed further. Two catalytically active forms with apparent relative molecular masses of 110,000 and 140,000 Da, respectively, were present in the purified preparation of the enzyme. Antibodies raised against the purified testis endopeptidase revealed by immunoblot both the 110- and 140-kDa forms in both rat testis and brain cortex extracts. The isolated enzyme was inhibited by metal chelators and divalent cations. Its activity, lost after preincubation with EDTA, was restored by low concentrations of Zn2+ and Mn2+, thus demonstrating the metallopeptidase nature of the enzyme. This endopeptidase also exhibited a high sensitivity to amastatin (100% inhibition at 20 microM), an aminopeptidase inhibitor. A substrate specificity study using physiologically important or synthetic peptides containing a processing dibasic site indicated that cleavage occurred selectively at the amino-terminal side of an arginine residue, independent of the nature of the basic doublet. The enzyme produced such a cleavage at the Arg-Lys doublet of somatostatin 28 (Km = 43 microM), at the Arg-Arg doublet of dynorphin A (Km = 6.45 microM) and atrial natriuretic factor (Km = 6.25 microM), and at the Lys-Arg doublet of preproneurotensin-(154-170) (Km = 17.3 microM). Moreover, cleavage efficiency was found to be higher for the larger substrates. The distinctive properties of this endopeptidase imply that this protein is a member of a novel class of proteolytic enzymes that may be involved in the endoproteolytic maturation of hormonal precursors.
 ...
PMID:Isolation and characterization of a dibasic selective metalloendopeptidase from rat testes that cleaves at the amino terminus of arginine residues. 829 57

The action of neuropeptides at the synapse is terminated through enzymatic degradation by membrane-bound proteases. We defined and purified membrane-bound proteases functioning at the initial stage of degradation of four neuropeptides. 1. Substance P-degrading endopeptidases isolated from the rat brain and pig striatum showed similar properties to those of endopeptidase-24.16 (neurolysin) except for cleavage sites of substance P. 2. LHRH fragment (1-5)-generating endopeptidases isolated from the neuroblastoma cells and rat brain showed similar properties to those of endopeptidase-24.15 (thimet oligopeptidase). 3. One of two dynorphin-degrading cysteine proteases isolated from neuroblastoma cells showed strict specificity toward the Arg-Arg residues. 4. Endopeptidase-24.11 (neprilysin) isolated from the rat brain was identified as a somatostatin-degrading enzyme.
 ...
PMID:[Membrane-bound proteases involved in neuropeptide degradation in the brain]. 836 28

A metalloendopeptidase (MEP) isolated from rabbit liver microsomes with substrate specificity for peptides containing Arg at the P1 and P4 positions has recently proved to be identical to soluble angiotensin-binding protein present in the cytosol. Here we describe the peptide-degrading specificity of MEP, determined using various bioactive peptides and novel fluorogenic substrates for the enzyme. MEP degraded oligopeptides, including bradykinin, alpha-neoendorphin, bovine adrenal medulla dodecapeptide, substance P, bombesin, neurotensin, and alpha-endorphin, but not polypeptides such as reduced lysozyme and histone H4, hence, MEP probably belongs to the family of endo-oligopeptidases. It cleaved most preferentially at the -Phe-Ser- bond of bradykinin (kcat/Km = 2.8 x 10(4) M-1.S-1) but did not cleave high molecular weight and low molecular weight kininogens, the precursors of bradykinin. MEP did not cleave angiotensin I, dynorphin A 1-13, somatostatin, and luteinizing hormone-releasing hormone, some of which are good substrates for metalloendopeptidase-24.15, metalloendopeptidase-24.16, N-arginine dibasic convertase, and yeast endopeptidase-24.15 related peptidase. An active site-directed inhibitor of metalloendopeptidase-24.15, N-[1-(R,S)-carboxyl-3-phenylpropyl]-Ala-Ala-Phe-p-aminobenzoate also had no effects on the amidolytic activity of MEP. Based on the cleavage sites of bioactive peptides and processing sites of vitamin K-dependent proproteins, intramolecularly quenched fluorogenic peptide substrates were newly synthesized. Among the thirteen substrates used, the most reactive was 2-aminobenzoyl-Ala-Arg-Val-Arg-Arg-Ala- Asn-Ser-2,4-dinitroanilinoethylamide (kcat/Km = 9.3 x 10(5) M-1.S-1). An angiotensin antagonist, [Sar1, Ala8]-angiotensin II, inhibited hydrolysis of the substrate by MEP in a competitive manner (Kl = 7.6 microM). MEP cleaved oligopeptides even on the carboxyl side of proline residue and these peptides are resistant to hydrolysis by the cytosol-derived proteasome, therefore MEP may participate in the catabolism of oligopeptides in the cytosol, together with other endo-oligopeptidases.
 ...
PMID:Substrate specificity of rabbit liver metalloendopeptidase and its new fluorogenic peptide substrates. 857 4

Transcripts of the somatostatin receptor subtypes sst3 and sst2 are expressed in meninges from rat brain as well as in immunocytochemical pure rat meningeal cells and rat fibroblasts in culture. mRNA of three other subtypes tested are absent or detected in trace amounts by reverse transcription-polymerase chain reaction. Presence of active receptors on the surface of meningeal cells and fibroblasts could be verified by direct visualisation of binding sites by affinity labelling with a somatostatin gold conjugate. The metabolically stable somatostatin agonist SMS 201-995 (octreotide) had a time-dependent effect on the [3H]thymidine incorporation by meningeal cells: after 2-5 h, the agonist inhibited cell proliferation to about 80% of controls, after 24 h proliferation was stimulated to about 150% of controls. Apart from being targets for somatostatin, meningeal cells had a high capacity to inactivate the peptide by proteolytic degradation. By analysis of cleavage sites and use of specific inhibitors, endopeptidase-24.11 ('enkephalinase', neutral endopeptidase, neprilysin, EC 3.4.24.11) was identified to be responsible for the initial catabolism of the peptide whereas aminopeptidase(s) truncated the fragments. Thus, meningeal cells express transcripts of multiple somatostatin receptor subtypes and produce peptidases that inactivate the neuropeptide somatostatin.
 ...
PMID:Meningeal cells are targets and inactivation sites for the neuropeptide somatostatin. 907 71

1. We have taken advantage of our recent development of highly potent and specific phosphinic inhibitors of endopeptidase 3.4.24.15 to examine the putative contribution of the enzyme in the secretion of A beta by HK293 transfected cells overexpressing the wild type and the Swedish (Sw) double mutated form of beta APP751. 2. First, we showed that HK293 cells contain a peptidase activity, the inhibition profile of which fully matches that of purified endopeptidase 3.4.24.15. Second, we established that the treatment of HK293 cells with specific phosphinic inhibitors leads to about 80% inhibition of intracellular endopeptidase 3.4.24.15 activity, indicating that these inhibitors penetrate the cells. 3. Metabolic labelling of wild type and Sw beta APP751-expressing cells, followed by immunoprecipitation of A beta-containing peptides, revealed the secretion of A beta and the intracellular formation of an A beta-containing 12 kDa product. 4. A beta secretion by Sw beta APP751 transfected cells was drastically enhanced when compared to cells expressing wild type beta APP751. This production was not affected by endopeptidase 3.4.24.15 inhibitors in either cell type. This correlates well with the observation that endopeptidase 3.4.24.15 does not cleave recombinant baculoviral Sw beta APP751, in vitro. 5. Our previous data indicated that endopeptidase 3.4.24.15 activity was reduced in the parietal cortex of Alzheimer's disease affected brains and that the enzyme probably participated, in this brain area, to the catabolism of somatostatin 1-14. However, the present work indicates that endopeptidase 3.4.24.15 does not seem to behave as a beta-secretase in HK293 transfected cells. Therefore, it is suggested that endopeptidase 3.4.24.15 could participate in the symptomatology, but probably not in the aetiology of Alzheimer's disease.
 ...
PMID:Examination of the role of endopeptidase 3.4.24.15 in A beta secretion by human transfected cells. 917

In this study we describe the partial purification and characterization of the HeLa cell oligopeptidase M or endopeptidase 3.4.24.16. The HeLa enzyme was isolated initially by its ability to hydrolyse a nonapeptide substrate (P9) which was cognate to the N-terminal cleavage site of preproTGF alpha. The enzyme was shown to be a metalloprotease as it was inhibited by Zn(2+)-chelating agents and DTT, and had an approximate molecular weight of 55-63 kD determined by gel filtration. Neurotensin, dynorphin A1-17 and GnRH1-9 were rapidly degraded by the enzyme while GnRH1-10 and somatostatin were not. Neurotensin was cleaved at the Pro10-Tyr11 bond, leading to the formation of neurotensin (1-10) and neurotensin (11-13). The K(m) for neurotensin cleavage was 7 microM and the Ki for the specific 24.16 dipeptide inhibitor (Pro-ile) was 140 microM which were similar to those observed from the human brain enzyme [Vincent et al. (1996): Brain Res 709:51-58]. Through the use of specific antibodies, the purified HeLa enzyme was shown to be oligopeptidase M. This enzyme and its closely related family member thimet oligopeptidase were shown to co-elute during the isolation procedure but were finally separated using a MonoQ column. Oligopeptidase M is located mainly in mitochondria though it was detected on the plasma membrane in an inactive form. The results obtained demonstrate the first recorded instance of this enzyme in human tissue cultured cells, and raise the issue of its function therein.
 ...
PMID:Characterization and localization of mitochondrial oligopeptidase (MOP) (EC 3.4.24.16) activity in the human cervical adenocarcinoma cell line HeLa. 925 87

The interaction between components of the nervous system and multiple target cells in the cutaneous immune system has been receiving increasing attention. It has been observed that certain skin diseases such as psoriasis and atopic dermatitis have a neurogenic component. Neuropeptides released by sensory nerves that innervate the skin and often contact epidermal and dermal cells can directly modulate functions of keratinocytes, Langerhans cells (LC), mast cells, dermal microvascular endothelial cells and infiltrating immune cells. Among these neuropeptides the tachykinins substance P (SP) and neurokinin A (NKA), calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP) and somatostatin (SOM) have been reported to effectively modulate skin and immune cell functions such as cell proliferation, cytokine production or antigen presentation under physiological or pathophysiological conditions. Expression and regulation of their corresponding receptors that are expressed on a variety of skin cells as well as the presence of neuropeptide-specific peptidases such as neutral endopeptidase (NEP) or angiotensin-converting enzyme (ACE) determine the final biological response mediated by these peptides on the target cell or tissue. Likewise, skin cells like keratinocytes or fibroblasts are a source for neurotrophins such as nerve growth factor that are required not only for survival and regeneration of sensory neurons but also to control responsiveness of these neurons to external stimuli. Therefore, neuropeptides, neuropeptide receptors, neuropeptide-degrading enzymes and neurotrophins participate in a complex, interdependent network of mediators that modulate skin inflammation, wound healing and the skin immune system. This review will focus on recent studies demonstrating the role of tachykinins, CGRP, SOM and VIP and their receptors and neuropeptide-degrading enzymes in mediating neurogenic inflammation in the skin.
 ...
PMID:Neuropeptides in the skin: interactions between the neuroendocrine and the skin immune systems. 958 47

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, the pathology of which becomes irreversible as it proceeds downstream of the disease cascade. Therefore, overcoming AD primarily requires early (presymptomatic) diagnosis, followed by preventive treatment. Since accumulation of amyloid beta peptide (A beta) in brain seems to play a central role AD pathogenesis, we established a new imaging technique to visualize A beta plaques in a mouse model of A beta amyloidosis in a non-invasive manner using a high-power MRI. This will open a new avenue to search for biochemical markers that correlate with the pathological parameters. We also found that a dimeric form of A beta, the quantity of which can be metabolically regulated by neprilysin, impairs in vivo neuronal plasticity, i.e. hippocampal long term potentiation. This suggests that reducing A beta dimers by upregulating neprilysin activity is likely to contribute to alleviation of memory-associated symptoms. Finally, we discovered that a neuropeptide, somatostatin, upregulates neuronal neprilysin activity. Because brain somatostatin expression is known to decline during aging, the finding indicates that the aging-induced downregulation of somatostatin may be a trigger for A beta accumulation leading to late-onset sporadic AD development and that somatostatin receptor(s) now emerge as pharmacological target candidates for the prevention and treatment of AD.
 ...
PMID:[Towards presymptomatic diagnosis, prevention and treatment of Alzheimer's disease]. 1565 Dec 88


<< Previous 1 2 3 4 5 Next >>