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)

ATP has recently emerged as an important proinflammatory mediator that has direct excitatory actions on sensory neurons through activation of ion channel-coupled P2X receptors. The purpose of the current work is to assess whether ATP alters the release of neuropeptides from sensory neurons and the receptors mediating this putative action. Exposing embryonic sensory neurons in culture to concentrations of ATP up to 300 microm did not increase the release of immunoreactive substance P or calcitonin gene-related peptide from sensory neurons. However, pre-exposing sensory neurons to 0.1 to 100 microm ATP prior to and throughout administration of 30 nM capsaicin resulted in a significant augmentation of release evoked by the vanilloid. This sensitizing action of ATP is blocked by suramin but not pyridoxal phosphate-6-azobenzene-2,4-disulfonic acid and is mimicked by the P2Y receptor agonists, 2-2-chloroadenosine triphosphate and UTP, but not by 2-(methylthio)adenosine 5'-triphosphate or alpha,beta-methyleneadenosine 5'-diphosphate. This profile of drug actions suggests that the sensitizing actions of ATP are mediated by P2Y receptors. Pretreating sensory neurons with bisindolylmaleimide I, a selective protein kinase C (PKC) inhibitor, attenuates the augmentation of capsaicin-induced peptide release by ATP, further implicating P2Y receptors in the actions of ATP. Immunoblotting also indicates the presence of P2Y2-like immunoreactive substance in embryonic dorsal root ganglia neurons. Together, these data support the notion that ATP acts at P2Y receptors in sensory neurons in a PKC-dependent manner to augment their sensitivity to other stimuli.
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PMID:ATP augments peptide release from rat sensory neurons in culture through activation of P2Y receptors. 1282 29

Some vagal afferent nerves are thought to mediate autonomic responses evoked by noxious oesophageal stimuli and participate in the perception of pain originating in the oesophagus. However, the vagal nociceptive nerve phenotypes implicated in this function have yet to be identified. In this study, nociceptive fibres were defined by the capacity to discriminate noxious mechanical stimuli (wide range of oesophageal distension with pressure up to 100 mmHg) and detect noxious chemical stimuli (the activators of capsaicin receptor TRPV1). Using immunohistochemical techniques with retrogradely labelled oesophagus-specific neurones and performing extracellular recordings from the isolated vagally innervated oesophagus, we show that in the guinea-pig, the vagus nerves supply the oesophagus with a large population of nociceptive-like afferent nerve fibres. Vagal nociceptive-like fibres in the guinea-pig oesophagus are derived from two embryonically distinct sources: neurones situated in the nodose vagal ganglia and neurones situated in the jugular vagal ganglia. Nodose (placode-derived) nociceptive-like fibres are exclusively C-fibres sensitive to a P2X receptors agonist and rarely express the neuropeptide substance P. In contrast, jugular (neural crest-derived) nociceptive-like fibres include both A-fibres and C-fibres, are insensitive to P2X receptors agonist and mostly express substance P. The non-nociceptive vagal tension mechanoreceptors are distinguished from nociceptors by their saturable response to oesophageal distension and by the lack of TRPV1. These tension mechanoreceptors are exclusively A-fibres arising from the nodose ganglion. We conclude that the vagus nerves supply the guinea-pig oesophagus with nociceptors in addition to tension mechanoreceptors. The vagal nociceptive-like fibres in the oesophagus comprise two distinct subtypes dictated by the ganglionic location of their cell bodies.
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PMID:Vagal afferent nerves with nociceptive properties in guinea-pig oesophagus. 1564 87

Non-adrenergic, non-cholinergic (NANC) inhibitory neurotransmission has been an area of intense interest in gut motor physiology, whereas excitatory NANC neurotransmission has received less attention. In order to further explore excitatory NANC neurotransmission, we performed conventional intracellular recordings from guinea-pig taenia caeci smooth muscle. Tissue was perfused with oxygenated Krebs solution at 35 degrees C and nerve responses evoked by either oral or aboral nerve stimulation (NS) (4 square wave pulses, 0.3 ms duration, 20 Hz). Electrical activity was characterized by slow waves upon which one to three action potentials were superimposed. Oral NS evoked an inhibitory junction potential (IJP) at either the valley or peak of the slow wave. Application of nifedipine (1 microM) abolished slow waves and action potentials, but membrane potential flunctuations (1-3 mV) and IJPs remained unaffected. Concomitant application of apamin (300 nM), a small-conductance Ca(2+)-activated K(+) channel blocker, converted the IJP to an EJP that was followed by slow IJP. Further administration of N(G)-nitro-l-arginine methyl ester (l-NAME, 200 microM), a nitric oxide synthase inhibitor, abolished the slow IJP without affecting the EJP, implying that the slow IJP is due to nitrergic innervation. The EJP was abolished by tetrodotoxin (1 microM), but was not significantly affected by atropine (3 microM) and guanethidine (3 microM) or hexamethonium (500 microM). Substance P (SP, 1 microM) desensitization caused slight attenuation of the EJP, but the EJP was abolished by desensitization with alpha,beta-methylene ATP (50 microM), a P2 purinoceptor agonist that is more potent than ATP at the P2X receptor subtype, suramin (100 microM), a non-selective P2 purinoceptor antagonist, and pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS, 100 microM) , a selective P2X purinoceptor antagonist. In contrast, the EJP was unaffected by MRS-2179 (2 microM), a selective P2Y(1) receptor antagonist. Aboral NS evoked an apamin- and l-NAME-sensitive IJP, but virtually no NANC EJP. These data suggest the presence of polarized excitatory purinergic neurotransmission in guinea-pig taenia caeci, which appears to be mediated by P2X purinoceptors, most likely the P2X(1) subtype.
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PMID:Excitatory purinergic neurotransmission in smooth muscle of guinea-pig [corrected] taenia caeci. 1567 92

The distribution and modulation of the P2X(3) receptor was studied in trigeminal ganglion neurons to provide insight into the role of ATP in craniofacial sensory mechanisms. Binding to the d-galactose specific lectin IB4 was found in 73% of P2X(3)-positive neurons while only 16% of IB4 neurons expressed P2X(3). Neurons expressing P2X(3) alone were significantly larger than IB4-or IB4/P2X(3)-positive neurons. Investigation of target-specificity revealed that 22% of trigeminal ganglion muscle afferent neurons were positive for P2X(3) versus 16% of cutaneous afferent neurons. Muscle P2X(3) afferents were significantly smaller than the overall muscle afferent population while P2X(3) cutaneous afferent neurons were not. Presumptive heteromeric (P2X(2/3)) muscle afferent neurons were also identified and comprised 77% of the P2X(3) muscle afferent population. Muscle afferent neurons co-expressed P2X(3) with either calcitonin gene-related peptide (15%) or substance P (4%). The number of P2X(3)-positive muscle afferent neurons significantly increased one and four days following complete Freund's adjuvant-induced masseter muscle inflammation, but significantly decreased after 12 days. These results indicate that within trigeminal ganglia: (1) the P2X(3) receptor is expressed in both small and medium-sized neurons; (2) the P2X(3) receptor is not exclusively expressed in IB4 neurons; (3) P2X(3) is co-expressed with neuropeptides; (4) differences in the proportion of cutaneous versus muscle P2X(3) afferents are not apparent. Trigeminal P2X(3) neurons therefore differ markedly from dorsal root ganglion P2X(3) afferents. This study also shows that deep tissue inflammation modulates expression of the P2X(3) receptor and thus may warrant exploration as a target for therapeutic intervention.
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PMID:Trigeminal P2X3 receptor expression differs from dorsal root ganglion and is modulated by deep tissue inflammation. 1615 75

Progressive loss of pain perception and cutaneous nerve fibers are frequently observed in diabetic patients. We evaluated the feasibility of using thy1-YFP mice that express the yellowish-green fluorescent protein (YFP) in all of their sensory/motor neurons for noninvasive monitoring of cutaneous nerve fiber loss during diabetes. Fluorescent fibers in skin sections from the leg of thy1-YFP mice stained positive for the neuron-specific protein gene product 9.5 (PGP9.5), indicating that the cutaneous fluorescent fibers are indeed nerve fibers. In diabetic thy1-YFP mice, significant small cutaneous nerve fiber loss in the leg was observed at 3 months following the onset of diabetes, but loss of heat-induced pain perception occurred as early as 1 month following the onset of diabetes, indicating that functional impairment of sensory nerves precedes cutaneous nerve fiber loss. Immunostaining of skin sections of mice killed at 6 months following the onset of diabetes showed that parallel to the loss of small fluorescent nerve fibers, there was a significant decrease in fibers stained positive for calcitonin gene-related peptide, substance P, and purinoreceptor subtype in diabetic thy1-YFP mice. These mice will be useful for noninvasive monitoring of cutaneous nerve fiber degeneration and loss of heat-induced pain perception during diabetes and for the assessment of efficacy of therapeutic treatment of diabetic neuropathy.
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PMID:Noninvasive monitoring of diabetes-induced cutaneous nerve fiber loss and hypoalgesia in thy1-YFP transgenic mice. 1624 33

Presynaptic ionotropic glutamate receptors are increasingly attributed a role in the modulation of sensory input at the first synapse of dorsal root ganglion (DRG) neurons in the spinal dorsal horn. Central terminals of DRG neurons express AMPA and NMDA receptors whose activation modulates the release of glutamate, the main transmitter at these synapses. Previous work, with an antibody that recognizes all low-affinity kainate receptor subunits (GluR5, 6, 7), provided microscopic evidence of presynaptic kainate receptors in unidentified primary afferent terminals in superficial laminae of the spinal dorsal horn (Hwang SJ, Pagliardini S, Rustioni A, Valtschanoff JG. Presynaptic kainate receptors in primary afferents to the superficial laminae of the rat spinal cord. J Comp Neurol 2001; 436: pp. 275-289). We show here that, although all such subunits may be expressed in these terminals, GluR5 is the subunit most readily detectable at presynaptic sites in sections processed for immunocytochemistry. We also show that the high-affinity kainate receptor subunits KA1 and KA2 are expressed in central terminals of DRG neurons and are co-expressed with low-affinity receptor subunits in the same terminals. Quantitative data show that kainate-expressing DRG neurons are about six times more likely to express the P2X(3) subunit of the purinergic receptor than to express substance P. Thus, nociceptive afferents that express presynaptic kainate receptors are predominantly non-peptidergic, suggesting a role for these receptors in the modulation of neuropathic rather than inflammatory pain.
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PMID:Presynaptic low- and high-affinity kainate receptors in nociceptive spinal afferents. 1636 Feb 75

Zinc ions (Zn(2+)) are known to modulate the functions of a variety of channels, receptors and transporters. We examined the effects of Zn(2+) on the reflex potentials evoked by electrical stimulation and responses to depolarizing agents in the isolated spinal cord of the neonatal rat in vitro. Zn(2+) at low concentrations (0.5-2 microM) inhibited, but at high concentrations (5 and 10 microM) augmented, a slow depolarizing component (slow ventral root potential). Zn(2+) had no effect on fast components (monosynaptic reflex potential; fast polysynaptic reflex potential). Unlike Zn(2+), strychnine (5 microM), a glycine receptor antagonist, and (S),9(R)-(-)-bicuculline methobromide (10 microM), a GABA(A) receptor antagonist, potentiated both fast polysynaptic reflex potential and slow ventral root potential. Zn(2+) (5 microM) did not affect depolarizing responses to glutamate and N-methyl-D-aspartate. Zn(2+) enhanced the substance P-evoked depolarization in the absence of tetrodotoxin (0.3 microM) but not in its presence. The dorsal root potential was inhibited by (S),9(R)-(-)-bicuculline methobromide (10 microM) but not by Zn(2+) (5 microM). The Zn(2+)-potentiated slow ventral root potential was inhibited by the N-methyl-D-aspartate receptor antagonists, ketamine (10 microM) and DL-2-amino-5-phosphaonovaleric acid (50 microM) but not by P2X receptor antagonists, pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (30 microM) and 2',3'-O-(2,4,6-trinitrophenyl)ATP (10 microM). Ketamine (10 microM) and DL-2-amino-5-phosphaonovaleric acid (50 microM) almost abolished spontaneous activities increased by Zn(2+). It is concluded that Zn(2+) potentiated slow ventral root potential induced by primary afferent stimulation, which was mediated by the activation of N-methyl-D-aspartate receptors but not by activation of P2X receptors or blockade of glycinergic and GABAergic inhibition. Zn(2+) does not seem to directly affect N-methyl-D-aspartate receptors. The release of glutamate from interneurons may play an important role in Zn(2+)-induced potentiation of slow ventral root potential in the spinal cord of the neonatal rat.
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PMID:Zinc modulates primary afferent fiber-evoked responses of ventral roots in neonatal rat spinal cord in vitro. 1636 Feb 85

P2X(7) is a receptor for extracellular nucleotides expressed by different normal cell types. P2X(7) triggering may result in stimulation of cell proliferation or induction of apoptosis depending on the level of activation. P2X(7) expression and function in B-cell chronic lymphocytic leukemia has been shown to correlate with disease severity. Here, we have asked the question of whether P2X(7) is expressed and functional in neuroblastoma, a pediatric tumor of neuroectodermal origin. P2X(7) was detected both in primary neuroblastoma tumors and in neuroblastoma cell lines. In the latter cells, P2X(7) stimulation by ATP was found to trigger (a) increased intracellular calcium fluxes, (b) plasma membrane depolarization, and (c) formation of a nonselective plasma membrane permeable pore. In contrast to the usual response typically observed in the majority of cell types, P2X(7) in vitro stimulation did not induce caspase-3 activation or apoptosis of neuroblastoma cells but rather supported their proliferation. Growth stimulation was partially due to substance P release from nucleotide-activated neuroblastoma cells. Therefore, neuroblastoma cells seem to have molded P2X(7) function to their advantage in two ways (i.e., by silencing P2X(7) proapoptotic activity and by coupling P2X(7) stimulation to release of locally acting trophic factors).
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PMID:The P2X7 receptor sustains the growth of human neuroblastoma cells through a substance P-dependent mechanism. 1642 24

Extracellular ATP is known to mediate fast, excitatory neurotransmission through activation of ionotropic P2X receptors. In this study, the localization of the P2X(2) receptor (P2X(2)R) subunit was studied in rat retina by using immunofluorescence immunohistochemistry and preembedding immunoelectron microscopy. The P2X(2)R was observed in large ganglion cells as well as in a subset of amacrine cells. Double labeling revealed that 96% of all P2X(2)R-immunoreactive amacrine cells showed gamma-aminobutyric acid (GABA) immunoreactivity. Subsets of P2X(2)R-immunoreactive amacrine cells expressed nitric oxide synthase and substance P; however, no colocalization was observed with choline acetyltransferase, vasoactive intestinal peptide, or tyrosine hydroxylase. Nearest-neighbor analysis confirmed that P2X(2)Rs were expressed by a heterogeneous population of amacrine cells. The synaptic connectivity of P2X(2)R amacrine cells was also investigated. It was interesting that P2X(2)R-immunoreactive amacrine cell dendrites stratified in the sublaminae of the inner plexiform layer occupied by cone, but not rod bipolar cell axon terminals. Immunoelectron microscopy revealed that P2X(2)-immunoreactive amacrine cell processes were associated with cone bipolar cell axon terminals as well as other conventional synapses in the inner plexiform layer. Taken together, these data provide further evidence for the involvement of extracellular ATP in neuronal signaling in the retina, particularly within cone pathways.
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PMID:P2X2 receptors on ganglion and amacrine cells in cone pathways of the rat retina. 1661 23

The contribution of glial cells in the regulation of the transfer of information in CNS and PNS is now increasingly recognized. Perisynaptic Schwann cells (PSCs), glial cells at the neuromuscular junction (NMJ), have proven to be an exceptionally important model for studying these roles. PSCs surround nerve terminals at the NMJ and are activated by transmitter release in a frequency-dependent manner. All of these receptors, except one type, are coupled to G proteins and can be regrouped into two categories: activators and modulators of PSCs. In the former category are muscarinic (unknown subtype) and purinergic receptors (P2X and P2Y). In the latter category are adenosine (A1), Substance P (NK-1) and CGRP receptors. All receptors coupled to G proteins induce the release of Ca2+ from internal stores. In return for this activation, PSCs modulate synaptic activity and short-term plasticity. In this review, we will focus on the role of purines in the induction of glial cell activity and their possible involvement in the modulation of synaptic transmission as a result of the synaptic-induced glial activity.
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PMID:Neuron-glia interactions at the neuromuscular synapse. 1680 33


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