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Overview

The nasal mucosa harbors sensory nerves containing neuropeptides such as substance P (SP), which are released by capsaicin. The neuropeptides are degraded by peptidases, e.g., neutral endopeptidase (NEP) that is present in the nasal mucosa. We studied the effect of enzymatically active recombinant NEP (rNEP) on neuropeptide-evoked secretion of nasal fluid and plasma exudation in rats. rNEP administered intranasally (i.n.) reduced the capsaicin-evoked nasal fluid secretion but failed to reduce the secretion evoked by SP (exogenous) under the experimental conditions used. rNEP reduced the increase in nasal plasma exudation evoked by capsaicin (endogenous neuropeptides). Because rNEP reduced neuropeptide-mediated nasal fluid secretion and plasma exudation in the rat, we suggest that peptidase activity in the nasal mucosa will determine the magnitude of the response to locally released neuropeptides.

01 Apr 1996·Biochemical JournalQ3 · BIOLOGY

Peptidyl vinyl sulphones: a new class of potent and selective cysteine protease inhibitors: S2P2 specificity of human cathepsin O2 in comparison with cathepsins S and L

Q3 · BIOLOGY

Article

Author: Okamoto, K ; Klaus, J L ; Palmer, J T ; Brömme, D ; Rasnick, D

Peptidyl vinyl sulphones are a novel class of extremely potent and specific cysteine protease inhibitors. They are highly active against the therapeutically important cathepsins O2, S and L. The highest kinact/Ki values exceed 107 M-1·s-1 for cathepsin S and 105 M-1·s-1 for cathepsins O2 and L. To study the primary specificity site of the novel human cathepsin O2 and the effectiveness of this novel class of inhibitors, a series of peptidyl vinyl sulphones with variations in the P2 residue was synthesized. Leucine in the P2 position was proven to be the most effective residue for cathepsin O2 and also for cathepsins S and L. Cathepsins O2 and S share a decreased accessibility towards P2 hydrophobic non-branched residues such as aminohexanoic acid (norleucine), methionine and oxidized methionine, but are distinguished by their different affinity towards phenylalanine in the P2 position. In contrast, cathepsin S accepts a broader range of hydrophobic residues in its S2 subsite than cathepsins O2 and L. The primary specificity-determining subsite pocket S2 in cathepsin O2 appears to be spatially more restricted than those of cathepsins S and L.

15 Mar 1996·Biochemical JournalQ3 · BIOLOGY

Molecular cloning, expression and potential functions of the human proteinase-activated receptor-2

Q3 · BIOLOGY

Article

Author: KAHN, Mark ; NELKEN, Nicholas A. ; PAYAN, Donald G. ; KONG, Wuyi ; BÖHM, Stephan K. ; COUGHLIN, Shaun R. ; BRÖMME, Dieter ; ANDERSON, David C. ; BUNNETT, Nigel W. ; CONNOLLY, Andrew ; SMEEKENS, Steven P.

We used PCR to amplify proteinase activated receptor-2 (PAR-2) from human kidney cDNA. The open reading frame comprised 1191 bp and encoded a protein of 397 residues with 83% identity with mouse PAR-2. In KNRK cells (a line of kirsten murine sarcoma virus-transformed rat kidney epithelial cells) transfected with this cDNA, trypsin and activating peptide (AP) corresponding to the tethered ligand exposed by trypsin cleavage (SLIGKV-NH2) induced a prompt increase in cytosolic calcium ion concentration ([Ca2+]i). Human PAR-2 (hPAR-2) resided both on the plasma membrane and in the Golgi apparatus. hPAR-2 mRNA was highly expressed in human pancreas, kidney, colon, liver and small intestine, and by A549 lung and SW480 colon adenocarcinoma cells. Hybridization in situ revealed high expression in intestinal epithelial cells throughout the gut. Trypsin and AP stimulated an increase in [Ca2+]i in a rat intestinal epithelial cell line (hBRIE 380) and stimulated amylase secretion in isolated pancreatic acini. In A549 cells, which also responded to trypsin and AP with mobilization of cytosolic Ca2+, AP inhibited colony formation. Thus PAR-2 may serve as a trypsin sensor in the gut. Its expression by cells and tissues not normally exposed to pancreatic trypsin suggests that other proteases could serve as physiological activators.

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