Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study examined the electrophysiological responses to antigen and to various stimuli in jejunal mucosa from rats sensitized to egg albumin with alum and pertussis adjuvants. Luminal antigen caused an immediate increase in short-circuit current, a measure of net ion transport, which was one of three different patterns. All were inhibited by the chloride channel blocker diphenyl-2-carboxylate, by chloride-free buffer, and by doxantrazole, a mast cell stabilizer. Depending on the pattern, the histamine-1 antagonist diphenhydramine, the 5-hydroxytryptamine-2 antagonist ketanserin, and the cyclooxygenase inhibitor piroxicam also reduced the responses. A neural component was indicated by inhibition of the responses to luminal antigen by the neurotoxin tetrodotoxin and by neonatal capsaicin treatment, which depletes substance P-containing nerves. In the absence of antigen, histamine and substance P caused increases in short-circuit current; the magnitude of these changes was significantly greater in tissues from sensitized animals than in controls. These data suggest that sensitization itself may result in hypersecretory responses to some inflammatory mediator and neurotransmitter substances.
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PMID:Allergic reactions of rat jejunal mucosa. Ion transport responses to luminal antigen and inflammatory mediators. 234 44

Substance P (SP), neurokinin A (NKA), neurokinin B (NKB), [Sar9, Met (O2)11]-SP (SMSP), senktide, [beta Ala8]-NKA(4-10) and neuropeptide gamma (NP gamma) all stimulate secretory responses in rat descending colon mucosa under voltage clamp conditions. Secretory responses (measured as short circuit current under voltage clamp conditions) were transient and those evoked by SP, SMSP, NKA and senktide were significantly reduced by pretreating tissues with the chloride channel blocker, diphenylamine carboxylate (DPC). Concentration-response curves showed varying degrees of sensitivity to tetrodotoxin (TTX). Senktide-induced secretion was virtually abolished by TTX, while NP gamma and [beta Ala8]-NKA(4-10) were not significantly altered. Rightward shifts of concentration-response curves were observed for SMSP, NKA and SP in TTX treated preparations compared with controls. NKA response curves in the presence of TTX were further inhibited by MEN10,207 and CP-96,345. GR71251, GR82334 and CP-96,345 all inhibited SMSP secretory responses with pA2 values of 5.8, 6.5 and 6.9 respectively. In conclusion three types of neurokinin receptor exist in preparations of rat colon mucosa and their relative location within neuronal and epithelial surfaces are discussed.
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PMID:Pharmacological characterisation of neurokinin receptors mediating anion secretion in rat descending colon mucosa. 823 96

1. We have examined the role of extracellular chloride in the mast cell secretion process. The immunologically-directed ligand, antibody to IgE (anti-IgE) required extracellular chloride ions for optimum secretion from rat peritoneal mast cells. In contrast, replacement of extracellular chloride did not alter the mast cell secretory response to compound 48/80, calcium ionophore A23187 or substance P. 2. Anti-IgE-stimulation of mast cells evoked a significant uptake of chloride ions compared to non-stimulated cells. The magnitude of chloride uptake correlated with the magnitude of stimulated histamine secretion. 3. Compound 48/80, substance P and A23187 did not alter the rate of chloride ion uptake, although these agents caused significant histamine secretion. 4. The Na+/K+/2Cl- cotransport inhibitor, furosemide, reduced the rate of anti-IgE-stimulated chloride uptake at a relatively high concentration (700 microM). However, the more potent Na+/K+/2Cl- cotransport inhibitors, bumetanide (100 microM) and piretanide (100 microM) had no effect on the stimulated chloride uptake. 5. Furosemide inhibited anti-IgE-induced histamine secretion, bumetanide potentiated the response and piretanide had no effect. This suggests that their respective action on histamine secretion are unrelated to inhibition of the Na+/K+/2Cl- carrier. 6. The chloride channel blocker, 5-nitro-2-((3-phenylpropyl)-amino)-benzoic acid (NPPB), reduced both anti-IgE-stimulated chloride uptake and the corresponding histamine secretion in a dose-dependent manner. The magnitude of the inhibitory action of the drug on these two cellular processes was comparable, implying that chloride channel activity is related to the mechanism of histamine secretion. 7. It is concluded that chloride uptake has a role in the control of Fc epsilon RI-mediated histamine secretion from rodent mast cells.
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PMID:Fc epsilon RI-mediated chloride uptake by rat mast cells: modulation by chloride transport inhibitors in relation to histamine secretion. 940 85

A novel G-protein-coupled receptor (GRL106) resembling neuropeptide Y and tachykinin receptors was cloned from the mollusc Lymnaea stagnalis. Application of a peptide extract from the Lymnaea brain to Xenopus oocytes expressing GRL106 activated a calcium-dependent chloride channel. Using this response as a bioassay, we purified the ligand for GRL106, Lymnaea cardioexcitatory peptide (LyCEP), an RFamide-type decapeptide (TPHWRPQGRF-NH2) displaying significant similarity to the Achatina cardioexcitatory peptide (ACEP-1) as well as to the recently identified family of mammalian prolactin-releasing peptides. In the Lymnaea brain, the cells that produce egg-laying hormone are the predominant site of GRL106 gene expression and appear to be innervated by LyCEP-containing fibers. Indeed, LyCEP application transiently hyperpolarizes isolated egg-laying hormone cells. In the Lymnaea pericardium, LyCEP-containing fibers end blindly at the pericardial lumen, and the heart is stimulated by LyCEP in vitro. These data confirm that LyCEP is an RFamide ligand for GRL106.
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PMID:The lymnaea cardioexcitatory peptide (LyCEP) receptor: a G-protein-coupled receptor for a novel member of the RFamide neuropeptide family. 982 40

Acute infectious diarrhoea continues to cause high morbidity and mortality worldwide. Although oral rehydration therapy has reduced the mortality associated with acute diarrhoea, stool volume often increases during the rehydration process. Therefore, for > 20 years there has been a search for agents that will directly inhibit intestinal secretory mechanisms and thereby reduce stool volume. The most obvious target for antisecretory therapy has been the chloride channel and second messengers within the enterocyte. So far, this search has been largely unrewarding, although recent evidence suggests that a new class of chloride channel blocker is effective in vitro but further evaluation in humans is required. In addition, research during the past decade has highlighted the importance of neurohumoral mechanisms in the pathogenesis of diarrhoea, notably the role of 5-hydroxtryptamine, substance P, vasoactive intestinal polypeptide and neural reflexes within the enteric nervous system. This new dimension of intestinal pathophysiology has already exposed possible novel targets for antisecretory therapy; namely, 5-hydroxytryptamine receptor antagonists, substance P antagonists and sigma-receptor agonists. There is also the possibility for potentiating the proabsorptive effects of endogenous enkephalins by using enkephalinase inhibitors. There now seems to be a real possibility that antisecretory therapy will become more widely available in the future.
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PMID:Novel agents for the control of secretory diarrhoea. 1521 18

Acute diarrhea is a major cause of morbidity and mortality worldwide. Infants and pre-school children are the most vulnerable in whom there are 2-3 million deaths each year as a result of the associated dehydration and acidosis. Although oral rehydration therapy has reduced mortality during the past 30 years ago, the search for agents that will directly inhibit intestinal secretory mechanisms and thereby reduce faecal losses in patients with high-volume watery diarrhea has continued for more than 20 years. A variety of potential targets for antisecretory agents have been explored which include loci within the enterocyte (the chloride channel, calcium-calmodulin) and other sites such as enteric nerves and endogenous mediators (such as 5-HT, prostaglandins). Although the potential of calcium-calmodulin inhibition has as yet not been realised, preliminary studies suggest that there are chloride channel blockers under development that will find a place in the management of secretory diarrheas. Recent work has highlighted the importance of neurohumoral mechanisms in the pathogenesis of acute diarrhea. Potentiation of the effects of endogenous enkephalin activity by enkephalinase inhibition has already produced a safe, effective anti-secretory drug, racecadotril. Speculative early work indicates that there may be a role for antagonists of 5-HT, substance P, and VIP receptors. There now seems to be a real possibility that antisecretory therapy will become more widely available in the future.
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PMID:Antisecretory drugs for diarrheal disease. 1669 63

The small intestine is in a dynamic state of secretion and absorption, the sum of which results in net absorption. Secretion is principally the result of chloride and bicarbonate extrusion through apical chloride channels after the activation of the second messengers cAMP, cGMP, and calcium. In addition to the cystic fibrosis transmembrane conductance regulator, several other candidate chloride channels have been identified and proposed to play a role in intestinal secretion, including the calcium-dependent chloride channel hCLCA1. Pathways leading to the negative control of secretion have been described that use cellular messengers, including inositol (3,4,5,6) tetrakisphosphate and phosphatidylinositol 3-kinase, which may act via basolateral potassium channels. The control of ion transport can also be viewed in terms of the enteric nervous system. The reflex neural pathways involved in enterotoxin-induced secretion have been substantiated and shown to involve 5-hydroxytryptamine, substance P, and the neurokinin 1 and 2 receptors in the sensory arm, and vasoactive intestinal peptide in the secretomotor efferents. Absorption of glucose in addition to active cotransport with sodium via the Na/glucose cotransporter protein has also been shown to occur passively through a carrier-mediated mechanism, using the membrane protein glucose transporter protein 2.
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PMID:Fluid and electrolyte transport in the small intestine. 1703 83

Interstitial cells of Cajal (ICC) associated with Auerbach's plexus in the small intestine, provide pacemaker activity to orchestrate peristalsis and mixing. Despite the close apposition between ICC and enteric nerves, little is known about the neural regulation of pacemaker activity. The present study pursues the hypothesis that substance P can affect pacemaker activity through action on non-selective cation channels. Cell-attached and inside-out patch clamp studies were performed on isolated ICC in short-term cultures that provided evidence that substance P increases open probability or initiates activity in non-selective cation channels in ICC. The single-channel conductance is approximately 25 pS and in the on-cell configuration the activity can occur in a rhythmic fashion. Patches contained 1-10 channels and were most often accompanied by a approximately 12 pS chloride channel that was also activated by substance P. In a recently developed preparation that allows patch clamping in ICC in their natural environment within tissue, i.e. in situ, the presence of the channel and substance P activation was confirmed. The non-selective cation channel is one of the channels that initiate intestinal pacemaker activity and the present study provides further single-channel data on this critical channel. Because of the close proximity of enteric motor and sensory nerves to ICC, these data provide a potential mechanism underlying neural regulation of pacemaker activity. The data also indicate that neurokinergic pharmacology is a promising avenue for excitation of the intestinal pacemaker system.
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PMID:Substance P activates a non-selective cation channel in murine pacemaker ICC. 1941 79

Airway smooth muscle hyperresponsiveness is a key component in the pathophysiology of asthma. Although calcium-activated chloride channel (CaCC) flux has been described in many cell types, including human airway smooth muscle (HASM), the true molecular identity of the channels responsible for this chloride conductance remains controversial. Recently, a new family of proteins thought to represent the true CaCCs was identified as the TMEM16 family. This led us to question whether members of this family are functionally expressed in native and cultured HASM. We further questioned whether expression of these channels contributes to the contractile function of HASM. We identified the mRNA expression of eight members of the TMEM16 family in HASM cells and show immunohistochemical evidence of TMEM16A in both cultured and native HASM. Functionally, we demonstrate that the classic chloride channel inhibitor, 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), inhibited halide flux in cultured HASM cells. Moreover, HASM cells displayed classical electrophysiological properties of CaCCs during whole cell electrophysiological recordings, which were blocked by using an antibody selective for TMEM16A. Furthermore, two distinct TMEM16A antagonists (tannic acid and benzbromarone) impaired a substance P-induced contraction in isolated guinea pig tracheal rings. These findings demonstrate that multiple members of this recently described family of CaCCs are expressed in HASM cells, they display classic electrophysiological properties of CaCCs, and they modulate contractile tone in airway smooth muscle. The TMEM16 family may provide a novel therapeutic target for limiting airway constriction in asthma.
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PMID:Functional expression of the TMEM16 family of calcium-activated chloride channels in airway smooth muscle. 2399 76

In humans and other mammalian species, lesions in the preoptic area of the hypothalamus cause profound sleep impairment, indicating a crucial role of the preoptic area in sleep generation. However, the underlying circuit mechanism remains poorly understood. Electrophysiological recordings and c-Fos immunohistochemistry have shown the existence of sleep-active neurons in the preoptic area, especially in the ventrolateral preoptic area and median preoptic nucleus. Pharmacogenetic activation of c-Fos-labelled sleep-active neurons has been shown to induce sleep. However, the sleep-active neurons are spatially intermingled with wake-active neurons, making it difficult to target the sleep neurons specifically for circuit analysis. Here we identify a population of preoptic area sleep neurons on the basis of their projection target and discover their molecular markers. Using a lentivirus expressing channelrhodopsin-2 or a light-activated chloride channel for retrograde labelling, bidirectional optogenetic manipulation, and optrode recording, we show that the preoptic area GABAergic neurons projecting to the tuberomammillary nucleus are both sleep active and sleep promoting. Furthermore, translating ribosome affinity purification and single-cell RNA sequencing identify candidate markers for these neurons, and optogenetic and pharmacogenetic manipulations demonstrate that several peptide markers (cholecystokinin, corticotropin-releasing hormone, and tachykinin 1) label sleep-promoting neurons. Together, these findings provide easy genetic access to sleep-promoting preoptic area neurons and a valuable entry point for dissecting the sleep control circuit.
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PMID:Identification of preoptic sleep neurons using retrograde labelling and gene profiling. 2851 46


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