Neuropeptides degradation

Neuropeptide degradation in vertebrates involves both soluble and membrane associated enzymes (1121 Similar mechanisms probably exist in insects. In fact, both soluble and membrane-bound proteolytic activities directed at bioactive peptides have been demonstrated in insect systems (107-1101 A vertebrate-like endopeptidase activity, the Zn-metalloendoprotease (endopeptidase-24 l 1), is present in the locust and is sensitive to the specific inhibitor, phosphoramidon (107-108.1111... 

Bunnett, N.W., Goldstein, S.M. and Nakazato, P. (1992). Isolation of a neuropeptide-degrading carboxypeptidase from the human stomach. Gastroenterology 102, 76-87. 

Endopeptidase-24.II (EC 3.4.24.11 NELP neutral endopeptidase neprilysin, enkephalinase) is a zinc-metalloproteinase, found both in soluble and plasma membrane forms. It is an important enzyme in neuropeptide degradation. Notable neuropeptide substrates include tachykinins (substance P, neurokinin A, neurokinin B), endothelins (ET-1, ET-2, ET-3), atrial natriuretic peptide, neurotensin, somatostatin and cholecystokinins. 

Extracellular degradation removes acetylcholine, the neuropeptides and ATP. Acetylcholine is rapidly hydrolyzed to choline and acetate by acetylcholinesterase. The enzyme is localized in both the presynaptic and the postsynaptic cell membrane and splits about 10,000 molecules of acetylcholine per second. 

Regulation of neuropeptide expression is exerted at several levels. Control of neuropeptide function is mediated by factors controlling rates of prepropeptide gene transcription, translation, peptide degradation and secretion (Fig. 18-11). On the scale of seconds to minutes, peptide secretion is not always coupled lock-step with classical transmitter release (example above). Peptides are inactivated by diffusion and by proteolysis, so it would be expected that inhibition of specific extracellular proteases... 

Bronchial epithelial cells participate in inflammation by releasing eicosanoids, peptidases, matrix proteins, cytokines, and nitric oxide. Epithelial shedding results in heightened airway responsiveness, altered permeability of the airway mucosa, depletion of epithelial-derived relaxant factors, and loss of enzymes responsible for degrading inflammatory neuropeptides. 

A variety of peptides are utilized in the nervous system as neurotransmitters. Unlike other neurotransmitters, which can be synthesized in various parts of the neuron like the axon terminals, neuropeptides are produced by gene transcription and translation. They may colocalize and be coreleased with ACh, monoamines, or amino acid neurotransmitters. Their receptors are metabotropic and may work through a variety of effector mechanisms. Neuropeptides are formed and degraded by a variety of peptidase enzymes. 

Hydrophilic hormones and other water-soluble signaling substances have a variety of biosynthetic pathways. Amino acid derivatives arise in special metabolic pathways (see p. 352) or through post-translational modification (see p. 374). Proteohormones, like all proteins, result from translation in the ribosome (see p. 250). Small peptide hormones and neuropeptides, most of which only consist of 3-30 amino acids, are released from precursor proteins by proteolytic degradation. 

Enzymes responsible for the synthesis and degradation of an expanding list that includes neurotransmitters, neuropeptides, and neurohormones... 

Neuropeptides are degraded by enzymes called neutral endopeptidases, which are present adjacent to neuropeptide receptors. Neutral endopeptidases regulate the neuropeptide-induced responses by modulating their levels. Inhibitors of these enzymes are being studied as a potential therapeutic agent for asthmatic disease. In... 

These serine proteases are used to remove pathogens by their hydrolytic activity. They degrade cell membrane proteins and connective tissue matrices by hydrolysis of extracellular matrix proteins such as fibronectin, type IV collagen and laminin, or solubilizing fibrous elastins [55, 56]. Immune cell proteases also are capable of cleaving cytokines, growth hormone, neuropeptides, and procoagulant proteins such as Factors X and V. 

There is ample documentation, obtained primarily in mammals, for the concept that the biosynthesis of the great majority of regulatory neuropeptides occurs by way of enzymatically cleaved large precursor molecules produced under the direction of mRNA templates. Future work will have to show to which extent these and the subsequent steps (posttranslational processing, release, and degradation of these products) also occur in insects. 

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