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)

Recent pathophysiological models of basal ganglia function in Parkinson's disease predict that specific neurochemical changes in the indirect pathway would follow the lack of stimulation of D(2) dopamine receptors. Post mortem studies of the basal ganglia in genetically modified mice lacking functional copies of the D(2) dopamine receptor gene allowed us to test these predictions. When compared with their congenic N(5) wild-type siblings, mice lacking D(2) receptors show an increased expression of enkephalin messenger RNA in the striatum, and an increased activity and expression of cytochrome oxidase I in the subthalamic nucleus, as expected. In addition, D(2) receptor-deficient mice display a reduced expression of glutamate decarboxylase-67 messenger RNA in the globus pallidus, as the basal ganglia model predicts. This reduction contrasts with the lack of change or increase in glutamate decarboxylase-67 messenger RNA expression found in animals depleted of dopamine after lesions of the mesostriatal dopaminergic system. Furthermore, D(2) receptor-deficient mice show a significant decrease in substance P messenger RNA expression in the striatonigral neurons which form the direct pathway. Finally, glutamate decarboxylase-67 messenger RNA expression in the basal ganglia output nuclei was not affected by mutations in the D(2) receptor gene, a fact that could probably be related to the absence of a parkinsonian locomotor phenotype in D(2) receptor-deficient mice. In summary, these findings provide compelling evidence demonstrating that the lack of endogenous stimulation of D(2) receptors is sufficient to produce subthalamic nucleus hyperactivity, as assessed by cytochrome oxidase I histochemistry and messenger RNA expression, and strongly suggest the existence of interactions between the basal ganglia direct and indirect pathways.
 ...
PMID:The indirect basal ganglia pathway in dopamine D(2) receptor-deficient mice. 1097 27

The neural control of the subcommissural organ (SCO) has been partially characterized. The best known input is an important serotonergic innervation in the SCO of several mammals. In the rat, this innervation comes from raphe nuclei and appears to exert an inhibitory effect on the SCO activity. A GABAergic innervation has also been shown in the SCO of the rat and frog Rana perezi. In the rat, GABA and the enzyme glutamate decarboxylase are involved in the SCO innervation. GABA is taken up by some secretory ependymocytes and nerve terminals, coexisting with serotonin in a population of synaptic terminals. Dopamine, noradrenaline, and different neuropeptides such as LH-RH, vasopressin, vasotocin, oxytocin, mesotocin, substance P, alpha-neoendorphin, and galanin are also involved in SCO innervation. In the bovine SCO, an important number of fibers containing tyrosine hydroxylase are present, indicating that in this species dopamine and/or noradrenaline-containing fibers are an important neural input. In Rana perezi, a GABAergic innervation of pineal origin could explain the influence of light on the SCO secretory activity in frogs. A general conclusion is that the SCO cells receive neural inputs from different neurotransmitter systems. In addition, the possibility that neurotransmitters and neuropeptides present in the cerebrospinal fluid may also affect the SCO activity, is discussed.
 ...
PMID:Neural input and neural control of the subcommissural organ. 1124 62

High-frequency stimulation (HFS) of the subthalamic nucleus (STN) is now recognized as an effective treatment for advanced Parkinson's disease, but the molecular basis of its effects remains unknown. This study examined the effects of unilateral STN HFS (2 hr of continuous stimulation) in intact and hemiparkinsonian awake rats on STN neuron metabolic activity and on neurotransmitter-related gene expression in the basal ganglia, by means of in situ hybridization histochemistry and immunocytochemistry. In both intact and hemiparkinsonian rats, this stimulation was found to induce c-fos protein expression but to decrease cytochrome oxidase subunit I mRNA levels in STN neurons. STN HFS did not affect the dopamine lesion-mediated overexpression of enkephalin mRNA or the decrease in substance P in the ipsilateral striatum. The lesion-induced increases in intraneuronal glutamate decarboxylase 67 kDa isoform (GAD67) mRNA levels on the lesion side were reversed by STN HFS in the substantia nigra, partially antagonized in the entopeduncular nucleus but unaffected in the globus pallidus. The stimulation did not affect neuropeptide or GAD67 mRNA levels in the side contralateral to the dopamine lesion or in intact animals. These data furnish the first evidence that STN HFS decreases the metabolic activity of STN neurons and antagonizes dopamine lesion-mediated cellular defects in the basal ganglia output structures. They provide molecular substrate to the therapeutic effects of this stimulation consistent with the current hypothesis that HFS blocks STN neuron activity. However, the differential impact of STN HFS on the effects of dopamine lesion among structures receiving direct STN inputs suggests that this stimulation may not cause simply interruption of STN outflow.
 ...
PMID:High-frequency stimulation of the subthalamic nucleus selectively reverses dopamine denervation-induced cellular defects in the output structures of the basal ganglia in the rat. 1207 9

Here we describe a novel technique for comparative analysis of the distributions of various neurochemicals visualized using multiple immunohistochemistry in the same brain slice. As an example, the distributions of tyrosine hydroxylase, substance P and glutamate decarboxylase in coronal slices of rat brains were compared. Each slice was divided into approximately 220,000-300,000 microareas at 20-microm intervals, and the immunohistochemical intensities of the three substances in each microarea were analyzed independently using a brain mapping analyzer; a microphotometry system previously developed in our laboratory (Sutoo et al., J. Neurosci. Methods, 1998; 85: 161-73). No significant differences between the distribution of each substance were observed in single- and triple-labeled slices. We believe that this method will facilitate the investigation of the functions of the central nervous system and the disorders thereof in various diseases.
 ...
PMID:A novel technique for quantitative immunohistochemical imaging of various neurochemicals in a multiple-stained brain slice. 1219 56

High levels of endogenous cholecystokinin (CCK) are present in the rat retina (Eskay & Beinfeld, 1982), but the cellular localization and physiological actions of CCK in the rat retina are uncertain. The goals of this study were to characterize the cells containing CCK, identify cell types that interact with CCK cells, and investigate the effects of CCK on rod bipolar cells. Rat retinas were labeled with antibody to gastrin-CCK (gCCK) using standard immunofluorescence techniques. Patch-clamp methods were used to record from dissociated rod bipolar cells from rats and mice. Gastrin-CCK immunoreactive (-IR) axons were evenly distributed throughout the retina in stratum 5 of the inner plexiform layer of the rat retina. However, the gCCK-IR somata were only detected in the ganglion cell layer in the peripheral retina. The gCCK-IR cells contained glutamate decarboxylase, and some of them also contained immunoreactive substance P. Labeled axons contacted PKC-IR rod bipolar cells, and recoverin-IR ON-cone bipolar cells. CCK-octapeptide inhibits GABA(C) but not GABA(A) mediated currents in dissociated rod bipolar cells.
 ...
PMID:Cholecystokinin-like immunoreactive amacrine cells in the rat retina. 1251 Oct 85

The expression of mRNA encoding for the 67 kilodalton isoform of glutamate decarboxylase (GAD67) was examined by in situ hybridization histochemistry in the entopeduncular nucleus (EP) of adult rats with a 6-hydroxydopamine unilaterally lesion of dopamine neurons. Our results provide original evidence that continuous or intermittent levodopa administration is equally effective at reversing the lesion-induced increase in GAD67 mRNA expression in the EP when compared with vehicle controls. To characterize the GABAergic interactions that may mediate levodopa-induced alterations in the EP, double-labeling in situ hybridization was conducted with a combination of GAD67 radioactive and preproenkephalin or preprotachykinin digoxigenin-labeled complementary RNA probes in the striatum. Levels of GAD67 mRNA labeling were significantly increased by intermittent, but not continuous levodopa. Analysis at the cellular level in a dorsal sector of the striatum revealed that GAD67 mRNA levels increased predominantly in preproenkephalin-unlabeled neuronal profiles, presumably striatal/EP neurons (+99.3%). Saturation analyses of (3)H-flunitrazepam binding to GABA(A) receptors in the EP showed that the increase in GAD67 mRNA in preproenkephalin-unlabeled neurons by intermittent levodopa paralleled a significant decrease in number of GABA(A) receptors (Bmax) in the EP ipsilateral to the lesion. Continuous levodopa failed to alter striatal GAD67 mRNA levels, or the number or affinity of GABA(A) receptors when compared with vehicle-treated controls. These results suggest the normalization of GAD gene expression in the EP by intermittent levodopa involves an increase in GABAergic inhibition by striatonigral/EP neurons of the direct pathway. Conversely, the effects of continuous levodopa on GAD mRNA levels in the EP do not appear to be mediated by GABA.
 ...
PMID:Normalization of glutamate decarboxylase gene expression in the entopeduncular nucleus of rats with a unilateral 6-hydroxydopamine lesion correlates with increased GABAergic input following intermittent but not continuous levodopa. 1466 39

Transient retinal ischemia induces loss of retinal ganglion cells, supporting the hypothesis that ischemic conditions contribute to the induction and progression of glaucoma. However, after 60 min of ischemia, also amacrine cells are lost from the inner nuclear layer. The main goal was to determine the relative vulnerability of various amacrine subpopulations by measuring the levels of transcripts that are known to be specifically expressed by different amacrine subpopulations. A 60-min ischemic period was administered to the rat eye by raising the intraocular pressure, followed by a reperfusion period lasting between 2 h and 4 weeks. Total RNA was isolated from the whole retina and expression levels were assessed by real-time quantitative polymerase chain reaction (qPCR). Retinal ischemia/reperfusion has differential effects on the levels of the various transcripts. Three main patterns of changes were identified. (i) A gradual decrease of transcript level without recovery was observed for parvalbumin; this transcript is expressed by the glycinergic AII cells. (ii) A gradual reduction to different levels at 72 h of reperfusion followed by a partial or complete recovery (glycine transporter 1, glutamate decarboxylase, calretinin, and several other transcripts). The glycinergic amacrine cell markers recovered to 65-75% of the control level, while the main GABAergic markers had completely recovered at 4 weeks. (iii) No significant changes of transcript levels were found for markers of several smaller GABAergic subpopulations [including substance P (Tac1), somatostatin, and others]. Expression levels of photoreceptor-, horizontal cell-, and bipolar cell-specific transcripts were not altered. These patterns were confirmed by a cluster analysis of the data. Based on gene expression levels, it may be concluded that amacrine cells are vulnerable to ischemic insults and that the glycinergic amacrine cells are relatively more sensitive to ischemia than the GABAergic population. In particular, the extensive loss of the parvalbumin-containing AII amacrine cells, which serve in the rod pathway, may have functional implications for vision under scotopic conditions. In the accompanying paper [F. Dijk and W. Kamphuis, An immunocytochemical study on specific amacrine subpopulations in the rat retina after ischemia, Brain Res. (2004).], the results are evaluated at the protein level by immunostaining for a selection of the amacrine cell markers.
 ...
PMID:Differential effects of ischemia/reperfusion on amacrine cell subtype-specific transcript levels in the rat retina. 1548 81

The respiratory neural network in the mammalian medulla oblongata shows rhythmic activity before birth. GABA and glycine are considered to be involved in control of respiratory rhythm. Recently we have demonstrated respiratory failure in glutamic acid decarboxylase (GAD) 67-deficient mice [Tsunekawa N, Arata A, Obata K (2005) Development of spontaneous mouth/tongue movement and related neural activity, and their repression in mouse fetus lacking glutamate decarboxylase 67. Eur J Neurosci 21:173-178]. To further evaluate the involvement of GABA and glycine in fetal respiratory function, we studied neural activities in brainstem-spinal cord blocks prepared from GAD65-/-:67-/- and vesicular GABA transporter (VGAT)-/-mice on embryonic day 14 (E14)-E15 and E18. In these knockout mice, the synthesis of GABA and the vesicular release of GABA and glycine are completely absent, respectively. Spontaneous respiratory discharges were observed in the ventral roots at the cervical cord (C) 4 level from wild-type mice but not from the knockout mice on E18. Administration of substance P induced C4 discharges in GAD65-/-:67-/- preparations but not in VGAT-/- preparations. C4 discharges were observed in the knockout mice on E14-E15, although the frequency was lower than that in the wild-type. Neuronal activities in the respiratory network of the E18 brainstem were recorded using a "blind" patch-clamp technique. Expiratory and inspiratory neurons with their characteristic firing patterns were observed in the wild-type fetuses. Strychnine reversed inspiratory-phase hyperpolarization to large depolarization in expiratory neurons. On the other hand, neurons in the same area of the knockout mice fired spontaneously without any rhythm. Substance P induced hyperpolarizing potentials in medullary neurons of GAD65-/-:67-/- mice. Further administration of strychnine induced large depolarizing potentials. Rhythmic activities were not observed in VGAT-/- mice even in the presence of substance P and strychnine. These results indicate that the lack of GABA and glycine impairs the function of the respiratory network in mouse fetuses and the impairment progresses with fetal age.
 ...
PMID:Respiratory activity in brainstem of fetal mice lacking glutamate decarboxylase 65/67 and vesicular GABA transporter. 1741 95

Electro-acupuncture (EA) is believed to be effective for alleviating motor symptoms in patients with Parkinson's disease. In a rat hemiparkinsonian model induced by unilateral transection of the medial forebrain bundle (MFB), the effects of EA stimulation were investigated. EA stimulation at a high frequency (100 Hz) significantly reduced apomorphine-induced rotational behavior. Tyrosine hydroxylase immunohistochemical staining revealed that EA at 100 Hz protected axotomized dopaminergic neurons from degeneration in the substantia nigra (SN). Moreover, high frequency EA reversed the axotomy-induced decrease in substance P content and increase in glutamate decarboxylase-67 (GAD 67) mRNA level in the midbrain; however, it did not affect the axotomy-induced increase in enkephalin content in the globus pallidus. These results suggest that the effects of high frequency EA on motor symptoms of Parkinsonian rats may involve restoration of the homeostasis of dopaminergic transmission in the basal ganglia circuit.
 ...
PMID:Electro-acupuncture stimulation improves motor disorders in Parkinsonian rats. 1954 45

To understand the functions of the neocortex, it is essential to characterize the properties of neurons constituting cortical circuits. Here, we focused on a distinct group of GABAergic neurons that are defined by a specific colocalization of intense labeling for both neuronal nitric oxide synthase (nNOS) and substance P (SP) receptor [neurokinin 1 (NK1) receptors]. We investigated the mechanisms of the SP actions on these neurons in visual cortical slices obtained from young glutamate decarboxylase 67-green fluorescent protein knock-in mice. Bath application of SP induced a nonselective cation current leading to depolarization that was inhibited by the NK1 antagonists in nNOS-immunopositive neurons. Ruthenium red and La(3+), transient receptor potential (TRP) channel blockers, suppressed the SP-induced current. The SP-induced current was mediated by G proteins and suppressed by D609, an inhibitor of phosphatidylcholine-specific phospholipase C (PC-PLC), but not by inhibitors of phosphatidylinositol-specific PLC, adenylate cyclase or Src tyrosine kinases. Ca(2+) imaging experiments under voltage clamp showed that SP induced a rise in intracellular Ca(2+) that was abolished by removal of extracellular Ca(2+) but not by depletion of intracellular Ca(2+) stores. These results suggest that SP regulates nNOS neurons by activating TRP-like Ca(2+)-permeable nonselective cation channels through a PC-PLC-dependent signaling pathway.
...
PMID:Substance P Activates Ca2+-Permeable Nonselective Cation Channels through a Phosphatidylcholine-Specific Phospholipase C Signaling Pathway in nNOS-Expressing GABAergic Neurons in Visual Cortex. 2531 39


<< Previous 1 2 3 4 5 Next >>