Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0033774 (pruritus)
 14,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proteinase-activated receptor-2 (PAR2) is a seven transmembrane spanning, G-protein-coupled receptor, present on the membrane of many cell types including keratinocytes. In skin, PAR2 is suggested to play a regulatory role during inflammation, epidermal barrier function, and pruritus. PAR2 is activated by trypsin-like proteases by a unique mechanism where cleavage of the receptor leads to the release of a small peptide, which activates the receptor as a tethered ligand. The endogenous activators of PAR2 on keratinocytes have not been identified as of yet. Potential candidates are kallikrein-related peptidases (KLKs) expressed by epidermal cells. Therefore, the ability of four human skin-derived KLKs was examined with regard to their capacity to activate PAR2 in vitro. PAR2 cleavage was followed by immunofluorescence analysis and functional activation by measurements of changes in intracellular calcium levels. We found that KLK5 and KLK14, but neither KLK7 nor KLK8, induced PAR2 signalling. We conclude that certain, but not all, epidermal KLKs are capable of activating PAR2. We could also show the coexpression of KLK14 and PAR2 receptor in inflammatory skin disorders. These in vitro results suggest that KLKs may take part in PAR2 activation in the epidermis and thereby in PAR2-mediated inflammatory responses, including epidermal barrier repair and pruritus. The role of KLKs in PAR2 activation in vivo remains to be elucidated.
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PMID:Activation of proteinase-activated receptor-2 by human kallikrein-related peptidases. 1762 93

Identifying the function of kallikrein-related peptidases (KLKs) in the epidermis has elicited great interest over recent decades. KLKs comprise 15 serine proteases, and their activities are regulated by complex and fine-tuned mechanisms involving the proteolytic activation cascade, endogenous inhibitors, and environmental factors. When the balance is disrupted, excessive or insufficient protease activity can impair epidermal barrier homeostasis. KLKs are involved in various events, such as skin inflammation, wound healing, pruritus, anti-bacterial activity, and viral susceptibility. One of the primary roles of KLKs, mainly KLK5 and KLK7, is physiological desquamation. Both proteases are also involved in the development of inflammatory skin diseases with barrier abnormalities, e.g., Netherton syndrome and atopic dermatitis (AD). In Netherton syndrome, unrestricted activity of KLK5 due to loss of the major endogenous inhibitor, lymphoepithelial Kazal-type-related inhibitor (LEKTI), destroys the component molecules of corneodesmosome, leading to Th2 and Th17 inflammation. Meanwhile, the increased activity of KLK7 in the hyperkeratotic lesions of chronic AD is suppressed by upregulated LEKTI. The functions and implications of other KLKs including KLK6 and KLK8 in healthy and diseased skin such as psoriasis represent an exciting but relatively unexplored area. Clarifying the function of epidermal KLKs will enable development of disease-specific biomarkers and new therapeutic strategies.
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PMID:Physiological and pathological roles of kallikrein-related peptidases in the epidermis. 3127 1