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

There is increasing evidence that the cutaneous nervous system modulates physiological and pathophysiological effects including cell growth and differentiation, immunity and inflammation as well as tissue repair. Both cutaneous nervous fibers and inflammatory cells are able to release neuromediators and thereby activate specific receptors on target cells in the skin or transient immunocompetent cells. Cutaneous neuromediators include classical neurotransmitters such as catecholamines and acetylcholine being released from the automatic nervous system or cutaneous cells. On the other hand neuropeptides including substance P, calcitonin gene related peptide (CRGP), vasointestinal peptide (VIP) or proopiomelanocortin (POMC) derived peptides such as alpha melanocyte stimulating hormone (alphaMSH) may be released from sensory or autonomic nerve fibers and several epidermal as well as dermal cells. Neuropeptides are known to activate a variety of cutaneous cells through high affinity neuropeptide receptors or by direct activation of intracellular G-protein signalling cascades. Via the modulation of transcription factor activation (NF-kappaB, AP-1, STAT-3) they regulate the expression of adhesion molecules and proinflammatory cytokines in different cells and thereby function as modulators of immune and inflammatory reactions. Accordingly, neuropeptides such as CGRP or alphaMSH in vitro were found to downregulate costimulatory molecule expression on dendritic cells and in vivo via the generation of suppressor T-lymphocytes to induce hapten specific tolerance. Proteinases such as tryptase or neural endopeptidase inactivate neuropeptides in the extracellular space or at the cell surface thereby terminating neuropeptide induced inflammatory or immune responses. Proteinase-activated receptors (PAR) are recently described receptors that may have high impact in regulating cutaneous neurogenic inflammation. In the skin PAR-2 being expressed on sensory neurons and endothelial cells is self activated by tethered peptide ligands that are exposed after extracellular amino-terminal cleavage by trypsin or mast cell tryptase. PAR-2 agonists were found to induce the release of CGRP and SP which mediate vasodilation, plasma extravasation as well as the expression of adhesion molecules on vascular endothelial cells and thus elicit neurogenic inflammation. These findings indicate that the neuromediator network including neuropeptide receptors as well as proteinases play an important role in the maintenance of tissue integrity and the regulation of inflammatory and immune responses in the skin.
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PMID:Neuromediators--a crucial component of the skin immune system. 1241 63

The neuroendocrine precursor protein proopiomelanocortin (POMC) and its derived neuropeptides are involved in a number of important regulatory processes in the central nervous system as well as in peripheral tissues. Despite its important role in controlling the local activation of melanocortin (MC) receptors, the extracellular proteolytic processing of POMC peptides has received little attention. The mechanisms relevant for controlling the bioavailability of adrenocorticotropin and melanocyte-stimulating hormones for the corresponding MC receptors in the skin by specific peptidases such as neprilysin (neutral endopeptidase; NEP) or angiotensin-converting enzyme (ACE) have been addressed in a number of recent investigations. This review summarizes the current body of knowledge concerning the qualitative and quantitative POMC peptide processing with respect to the action and specificity of NEP and ACE and discusses relevant recent analytical methodologies.
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PMID:Monitoring neuropeptide-specific proteases: processing of the proopiomelanocortin peptides adrenocorticotropin and alpha-melanocyte-stimulating hormone in the skin. 1698 56

The skin including the microvascular endothelium is an established peripheral source and target of the immunomodulatory proopiomelanocortin (POMC) peptides ACTH and alpha-MSH. Whereas intracellular POMC peptide generation is well characterized, less is known on their extracellular processing in peripheral tissues by the neuropeptide-specific zinc metalloproteases neprilysin (NEP) and angiotensin-converting enzyme (ACE). This may locally control POMC peptide bioavailability and activation of ACTH/alpha-MSH-specific melanocortin receptors (MCs). In a cell-free system, endothelial cell (EC) membranes prepared from ACE(high)/NEP(low)-expressing primary human dermal microvascular ECs and the ACE(low)/NEP(high) expressing EC line HMEC-1 degraded ACTH(1-39) over time, resulting in temporary increased alpha-MSH immunoreactivity. Matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy peptide mapping and electrospray ionization-mass spectroscopy sequencing identified several stable fragments generated from ACTH(1-39), ACTH(1-24), and alpha-MSH by EC membranes or recombinant NEP and ACE. Whereas some fragments could be assigned to a cell-specific NEP or ACE activity, other degradation products require additional enzyme activity. Pharmacological NEP inhibition enhanced the ACTH and alpha-MSH-mediated activation of EC ectopically expressing MC(1). Likewise, selected peptides such as alpha-MSH(2-12) generated from ACTH(1-39) and alpha-MSH by recombinant NEP displayed equipotent MC(1)-activating properties in vitro and antiinflammatory activity in murine allergic contact dermatitis in vivo as compared with the parental peptides. Thus, NEP and ACE significantly contribute to the EC processing of stress hormones (ACTH) and antiinflammatory peptides (alpha-MSH), which modulates MC(1) activation but does not completely inactivate the peptide ligand. Because NEP and ACE are regulated by inflammatory mediators and UV light, this may be important for ACTH/MSH-modulated skin inflammation.
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PMID:Terminating the stress: peripheral peptidolysis of proopiomelanocortin-derived regulatory hormones by the dermal microvascular endothelial cell extracellular peptidases neprilysin and angiotensin-converting enzyme. 1736 57


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