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

We characterized a subpopulation of dorsal root ganglion (DRG) sensory neurons that were previously identified as preferential targets of enkephalins. This group, termed P-neurons after their "pear" shape, sequentially required nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) for survival in vitro during different developmental stages. Embryonic P-neurons required NGF, but not bFGF. NGF continued to promote their survival, although less potently, up to postnatal day 2 (P2). Conversely, at P5, they needed bFGF but not NGF, with either factor having similar effects at P2. This trophic switch was unique to that DRG neuronal group. In addition, neither neurotrophin-3 (NT-3) nor brain-derived neurotrophic factor influenced their survival during embryonic and postnatal stages, respectively. The expression of NGF (Trk-A) and bFGF (flg) receptors paralleled the switch in trophic requirement. No single P-neuron appeared to coexpress both Trk-A and flg. In contrast, all of them coexpressed flg and substance P, providing a specific marker of these cells. Immunosuppression of bFGF in newborn animals greatly reduced their number, suggesting that the factor was required in vivo. bFGF was present in the DRG and spinal cord, as well as in skeletal muscle, the peripheral projection site of P-neurons, as revealed by tracer DiIC(18)3. The lack of requirement of NT-3 for survival and immunoreactivity for the neurofilament of 200 kDa distinguished them from muscle proprioceptors, suggesting that they are likely to be unmyelinated muscle fibers. Collectively, their properties indicate that P-neurons constitute a distinct subpopulation of sensory neurons for which the function may be modulated by enkephalins.
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PMID:A sensory neuron subpopulation with unique sequential survival dependence on nerve growth factor and basic fibroblast growth factor during development. 1169 99

In the present study, the co-localisation of substance P (SP) with the vanilloid receptor TRPV1 and the neurotrophin receptor tyrosine kinase trkA was analysed in airway-specific murine dorsal root ganglion (DRG) neurons. DRG neurons labelled with Fast Blue were predominantly found at the segmental levels T2-T5. Immunoreactivity for the receptor TRPV1 was localized to 12% of Fast Blue labelled DRG neurons. Double-labelling immunohistochemistry revealed that a substantial number of them also co-express SP (7.6 +/- 1.1% (mean +/- S.E.M.)), whereas neurons with immunoreactivity for TRPV1 only were found in 4.4 +/- 1.3% of the retrogradely labelled neuronal population. Further analysis of retrogradely labelled neurons showed that their majority expressed trkA (62.8 +/- 1.4%), neurofilament protein 68-kDa (64.8 +/- 1.5%) or glutamate alone (19.5 +/- 1.9%). SP was always expressed in trkA-positive neurons. Based on the extent of co-localization of SP with the receptors TRPV1 and trkA in DRG airway neurons, the present study indicates that the DRG pathway may have effects on the magnitude of neurogenic inflammation in airway diseases such as asthma.
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PMID:Substance P expression in TRPV1 and trkA-positive dorsal root ganglion neurons innervating the mouse lung. 1552 99

Necdin is a multifunctional signaling protein that stabilizes terminal differentiation of postmitotic neurons. The human necdin gene in chromosome 15q11-q12 is maternally imprinted, paternally transcribed, and not expressed in Prader-Willi syndrome, a human genomic imprinting-associated neurodevelopmental disorder. Although necdin-deficient mice display several abnormal phenotypes reminiscent of this syndrome, little is known about molecular mechanisms that lead to the neurodevelopmental defects. Here, we demonstrate that paternally expressed necdin is required for physiological development of nerve growth factor (NGF)-dependent sensory neurons. Mouse embryos defective in the paternal necdin allele displayed absent necdin expression in the dorsal root ganglia, in which the tropomyosin-related kinase A (TrkA) receptor tyrosine kinase and the p75 neurotrophin receptor were expressed in a normal manner. Necdin interacted with both TrkA and p75 to facilitate the association between these receptors. NGF-induced phosphorylation of TrkA and mitogen-activated protein kinase was significantly diminished in the necdin-null sensory ganglia. Furthermore, the mice lacking the paternal necdin allele displayed augmented apoptosis in the sensory ganglia in vivo and had a reduced population of substance P-containing neurons. These mutant mice showed significantly high tolerance to thermal pain, which is often seen in individuals with Prader-Willi syndrome. These results suggest that paternally expressed necdin facilitates TrkA signaling to promote the survival of NGF-dependent nociceptive neurons.
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PMID:Disruption of the paternal necdin gene diminishes TrkA signaling for sensory neuron survival. 1604 86

C57BLKS db/db (db/db) mice develop a neuropathy with features of human type 2 diabetic neuropathy. Here, we demonstrate that these mice develop transient mechanical allodynia at the early stage of diabetes. We hypothesized that nerve growth factor (NGF), which enhances the expression of key mediators of nociception (i.e. substance P [SP] and calcitonin gene-related peptide), contributes to the development of mechanical allodynia in these mice. We found that NGF, SP, and calcitonin gene-related peptide gene expression is upregulated in the dorsal root ganglion (DRG) of db/db mice before or during the period that they develop mechanical allodynia. There were more small- to medium-sized NGF-immunopositive DRG neurons in db/db mice than in control db+ mice; these neurons also expressed SP, consistent with its role in nociception. Nerve growth factor expression in the hind paw skin was also increased in a variety of dermal cell types and nerve fibers, suggesting the contribution of a peripheral source of NGF to mechanical allodynia. The upregulation of NGF coincided with enhanced tropomyosin-related kinase A receptor phosphorylation in the DRG. Finally, an antibody against NGF inhibited mechanical allodynia and decreased the numbers of SP-positive DRG neurons in db/db mice. These results suggest that inhibition of NGF action is a potential strategy for treating painful diabetic neuropathy.
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PMID:Nerve growth factor mediates mechanical allodynia in a mouse model of type 2 diabetes. 1981 94

Airway hyperresponsiveness is the hallmark of allergic asthma and caused by multiple factors. Nerve growth factor (NGF), a neurotrophin, is originally known for regulation of neural circuit development and function. Recent studies indicated that NGF contributes to airway hyperresponsiveness and pathogenesis of asthma. The objective of this study is to develop a small interfering RNA against NGF to attenuate airway hyperresponsiveness and further elucidate the underlying mechanism. In a murine model of allergic asthma, the ovalbumin-sensitized mice were intratracheally delivered small interfering RNA against NGF or administered an inhibitor targeting NGF receptor, tropomyosin-related kinase A, as a positive treatment control. In this study, knockdown NGF derived from pulmonary epithelium significantly reduced airway resistance in vivo. The levels of NGF, proinflammatory cytokines and infiltrated eosinophils in airway were decreased in small interfering RNA against NGF group but not in tropomyosin-related kinase A inhibitor and mock siRNA group. Furthermore, induction of neuropeptide (substance P) and airway innervation were mediated by NGF/tropomyosin-related kinase A pathway. These findings suggested that NGF targeting treatment holds the potential therapy for antigen-induced airway hyperresponsiveness via attenuation of airway innervation and inflammation in asthma.
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PMID:Small interfering RNA targeting nerve growth factor alleviates allergic airway hyperresponsiveness. 2471 23