SUMMARY1. Substance P (6-25-25 p-mole) produced dose-dependent flare and wheal responses when injected intradermally into the volar surface of the human forearm.2. The maximum flare response was obtained within the first 3 min of injection and declined thereafter. The wheal response reached a maximum after 12 min following the injection.3. Only those peptides having one or more basic residues in the N-terminal region were effective in producing a flare reaction. Eledoisin-related peptide and SP1 , were 17 and 7 times less active than substance P respectively, whilst [D-pro2, D-phe7, D-trp9]SP1 -1 was twice as active. The N-terminal tetrapeptide, SP1 4 and eledoisin were inactive in the dose range tested.4. Wheal-producing activity was not dependent on the presence of basic residues and the rank order of relative potencies was: physalaemin ( response in the dose range tested.5. Substance P was approximately equi-active with poly-L-arginine in the production of wheal and flare and both of these agents were about 10 times more potent than histamine. Adenosine triphosphate (25-400 n-mole) produced dose-dependent wheal and flare responses and was 10,000 times less potent than substance P. Pre-treatment of the subjects with the H, histamine antagonist, chlorpheniramine, (20 mg i.v.) reduced the wheal and flare responses to substance P.6. Local anaesthetic injection into the skin reduced the spread of the flare response but did not affect the development of the wheal response.7. Pre-treatment of the skin with capsaicin reduced the flare but not the wheal response to intradermal injection of histamine.8. The results are discussed in relation to the mechanism of the 'axon reflex' vasodilatation in skin. This is thought to involve mast cells in addition to substance P-containing primary afferent neurones.
SUMMARY1. Substance P (SP) induces histamine release from isolated rat peritoneal mast cells at concentrations of 0-1-10 /tM.2. Inhibitors of glycolysis and oxidative phosphorylation prevent the release of histamine induced by SP. 3. Cells heated to 47 'C for 20 min release histamine when treated with an agent causing cell lysis but fail to release histamine in response to SP.4. SP does not release histamine by interacting with cell-bound IgE.5. Histamine release by SP is rapid, with more than 90 % of the response occurring within 1 min of the addition of the peptide to mast cells at 37 'C. 6. Substance P, unlike antigen-antibody or compound 48/80, does not show enhanced release of histamine when calcium (0 1-1 mM) is present in the extracellular medium but calcium increases the response to SP when the ion is added after the peptide. Extracellular calcium (01-1 mM), magnesium (1-10 mM) and cobalt (0-01-0-1 mM) all inhibit SP-induced histamine release when added before the peptide.Pre-treatment of the cells with EDTA (10 mM) and washing in calcium-free medium inhibits the histamine release induced by SP.7. Histamine release induced by SP was optimum at an extracellular pH of 7-2. 8. A number of peptides structurally related to SP were examined for histaminereleasing activity. At the concentrations tested, the N-terminal dipeptides Lys-Pro and Arg-Pro, tuftsin, physalaemin, eledoisin, SP31,, Phe7]-SP6 -1 were all found to be inactive. The relative activities of the other peptides were:
Abstract:In the rat adrenal gland, we previously observed that SNAP-25 is not restricted to the plasmalemma in noradrenergic cells as it is in adrenergic cells, and hypothesized that SNAP-25 isoform expression is different in the two phenotypes. Expression of SNAP-25 isoforms and SNAP-23 was examined by immunoblotting, immunofluorescence, and RT-PCR. Amplifications of SNAP-25 mRNAs were combined with Southern hybridization, restriction enzyme analysis, and sequencing of cloned PCR products to compare SNAP-25 isoform expression in rat and bovine adrenal glands. SNAP-25 and SNAP-23 mRNA and protein are expressed in the glands; SNAP-23 is enriched in the adrenal cortex, whereas SNAP-25 is restricted to the adrenal medulla. Furthermore, high levels of SNAP-25 and low levels of SNAP-23 are observed in the PC12 cells, whereas both SNAP-25 and SNAP-23 are expressed in adrenal medullary cultures. In all extracts, the SNAP-23 mRNA corresponded to SNAP-23a. SNAP-25a is the major form expressed in rat adrenal glands (75%), as it is in PC12 cells (80%), but both SNAP-25a and SNAP-25b (40% vs. 60%) are expressed in bovine adrenal medulla in situ and in culture. In addition, an enriched population of adrenergic cells (93%) expressed a higher level of SNAP-25b (70%), suggesting that this isoform may not be restricted to fast neurotransmission. Key Words: SNAP-25 isoforms-SNAP-23-Neuroendocrine-Chromaffin cells-Adrenergic-Noradrenergic. J. Neurochem. 72, 363-372 (1999).SNAP-25 (synaptosomal associated protein of 25 kDa) is implicated in the docking and fusion of vesicles at the plasma membrane during both constitutive and regulated exocytosis in neurons and neuroendocrine cells (Sollner et al., 1993;Sudhof et al., 1993;Sollner and Rothman, 1994). The functional importance of SNAP-25 in neurotransmitter release from small synaptic vesicles (SSVs) and large dense-core vesicles (LDCVs) is underscored by evidence that it is a specific target of botulinum toxins A and E, which selectively block neurotransmission (Ahnert-Hilger and Weller, 1993;Blasi et al., 1993;Schiavo et al., 1993;Binz et al., 1994;Roth and Burgoyne, 1994). In the hypothesis currently proposed for vesicle-docking, soluble N-ethylmaleimide-sensitive fusion (NSF) protein and the NSFassociated proteins (SNAPs) form a fusion complex with SNAP-25 and syntaxin, the target receptors or t-SNAREs on the plasma membrane, and synaptobrevin and synaptotagmin, the vesicle membrane receptors or v-SNAREs (Sollner et al., 1993;Sollner and Rothman, 1994;Schiavo et al., 1997). SNAP-25 and syntaxin have been recently reported on synaptic vesicles (Walch-Solimena et al., 1995;Kretzschmar et al., 1996) and chromaffin granules (HohneZell and Gratzl, 1996;Tagaya et al., 1996), suggesting that the targeting role of these proteins may be oversimplified. The existence of multiple receptors and isoforms of many of these fusion complex proteins may contribute to vesicletarget specificity necessary for distinct biological functions requiring vesicle fusion (Bark et al., 1995;Linial, 1997).Rec...
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