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1.
The cellular localization of the tyrosine-specific protein kinase p62c-yes
, the product of the proto-oncogene c-yes, has been examined in the striatonigral neurons which interconnect the rat neostriatum and substantia nigra. Although p62c-yes
was more enriched in the neostriatum than in the substantia nigra, excitotoxin-induced necrosis of nerve cells in the neostriatum led to 50–60% decreases of p62c-yes
both in the lesioned neostriatum and in the ipsilateral substantia nigra. Hence, the p62c-yes
tyrosine kinase is present both in the cell body region and in the axonal and nerve terminal region of the striatonigral neurons. This localization indicates that the enzyme may be involved in both presynaptic and postsynaptic functions in mammalian forebrain neurons.Special issue dedicated to Dr. Paul Greengard. 相似文献
2.
The globus pallidus externus (GP) is a nucleus of the basal ganglia (BG), containing GABAergic projection neurons that arborize widely throughout the BG, thalamus and cortex. Ongoing work seeks to map axonal projection patterns from GP cell types, as defined by their electrophysiological and molecular properties. Here we use transgenic mice and recombinant viruses to characterize parvalbumin expressing (PV+) GP neurons within the BG circuit. We confirm that PV+ neurons 1) make up ~40% of the GP neurons 2) exhibit fast-firing spontaneous activity and 3) provide the major axonal arborization to the STN and substantia nigra reticulata/compacta (SNr/c). PV+ neurons also innervate the striatum. Retrograde labeling identifies ~17% of pallidostriatal neurons as PV+, at least a subset of which also innervate the STN and SNr. Optogenetic experiments in acute brain slices demonstrate that the PV+ pallidostriatal axons make potent inhibitory synapses on low threshold spiking (LTS) and fast-spiking interneurons (FS) in the striatum, but rarely on spiny projection neurons (SPNs). Thus PV+ GP neurons are synaptically positioned to directly coordinate activity between BG input nuclei, the striatum and STN, and thalamic-output from the SNr. 相似文献
3.
Joseph T. Coyle David Jacobowitz David Klein Julius Axelrod 《Developmental neurobiology》1973,4(5):461-470
Explants of substantia nigra and corpus striatum obtained from newborn rats were maintained in tissue culture for up to six days. Explants of substantia nigra exhibited a net increase in the ability to take up H3-dopamine, a process associated with the dopaminergic neurons; in contrast, the explants of corpus striatum showed a rapid loss in this ability to accumulate H3-dopamine. After three days in culture, the specific activity of tyrosine hydroxylase and monoamine oxidase had decreased 50% in explants of substantia nigra. A medium including fetal calf serum and chick embryo extracts was necessary for the increase in H3-dopamine uptake, and nerve growth factor had an inhibitory effect. Histofluorescent examination of nigral explants cultured for three days indicated morphologically normal dopaminergic neurons. 相似文献
4.
Enrico Sanna Costantino Motzo Marcello Usala Davide Pau Elisabetta Cagetti Giovanni Biggio 《Journal of neurochemistry》1998,70(6):2539-2544
Abstract: Expression of rat brain γ-aminobutyric acid type A (GABAA) receptors in Xenopus laevis oocytes can be achieved by injection of the oocytes with synaptosomes. This approach has now been applied to evaluate changes in the function of nigral GABAA receptors after degeneration of the striatonigral GABAergic pathway induced by the unilateral infusion of kainic acid into the rat striatum. Ten days after striatal injection, synaptosomal membranes were prepared from the substantia nigra and introduced into oocytes. Nigral GABAA receptors incorporated into the oocyte cell membrane were then characterized electrophysiologically under voltage-clamp conditions. The maximal amplitude of GABA-induced Cl? currents in oocytes injected with synaptosomes from denervated substantia nigra was twice that observed in oocytes injected with synaptosomes from control substantia nigra. The concentration of GABA required for the half-maximal response did not differ between the two groups of oocytes. In addition, the potentiation of GABA-induced currents by the benzodiazepine diazepam (1 µM) and the steroid derivative allopregnanolone (3 µM) was increased by ~65 and 60%, respectively, in oocytes injected with synaptosomes from denervated substantia nigra compared with those injected with control synaptosomes. The concentrations of diazepam and allopregnanolone giving half-maximal responses were not affected by denervation. In contrast, the inhibitory effects of the benzodiazepine receptor inverse agonists FG 7142 (10 µM) and 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylic acid ethyl ester (1 µM) were reduced by 48 and 38%, respectively, after denervation. These results indicate that the up-regulation of nigral GABAA receptors induced by degeneration of the striatonigral GABAergic pathway is associated with an increased efficacy of positive allosteric modulators, such as benzodiazepines and steroids, and with a reduced efficacy of negative allosteric modulators such as β-carbolines. 相似文献
5.
DARPP-32 and Phosphatase Inhibitor-1, Two Structurally Related Inhibitors of Protein Phosphatase-1, Are Both Present in Striatonigral Neurons 总被引:6,自引:1,他引:5
Angus C. Nairn Hugh C. Hemmings Jr. S. Ivar Walaas Paul Greengard 《Journal of neurochemistry》1988,50(1):257-262
DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein of Mr = 32,000) and phosphatase inhibitor-1, two previously characterized inhibitors of protein phosphatase-1, were identified in both the neostriatum and the substantia nigra. Phosphatase inhibitor-1 was partially purified from bovine caudate nucleus and found to be distinct from DARPP-32 in some of its biochemical properties. The neuronal localization of DARPP-32 and phosphatase inhibitor-1 within the rat neostriatum and substantia nigra was investigated by studying the effects of kainic acid. Injection into the neostriatum of kainic acid, which destroys striatonigral neurons and striatonigral fibers, decreased the amounts of DARPP-32 and phosphatase inhibitor-1 to the same extent, both in the lesioned neostriatum and in the ipsilateral substantia nigra. The specific activity of protein phosphatase-1 in the neostriatum was unaffected by kainic acid. The results indicate that, in rat brain, DARPP-32 and phosphatase inhibitor-1 are both present in striatal neurons and in striatonigral fibers, and that they probably coexist in at least a subpopulation of striatonigral neurons. In contrast, protein phosphatase-1 does not appear to be enriched in any specific neuronal subpopulation in the neostriatum. 相似文献
6.
Bilateral electrolytic lesion of the striatonigral pathways (which convey massive afferents to the substantia nigra) caused a marked lowering of alpha-neo-endorphin (alpha-Neo) and dynorphin A(1-8) [Dyn A(1-8)] levels in the substantia nigra without affecting the alpha-Neo content in the ventral tegmental area. Moreover, unilateral infusion of the axon sparing neurotoxin ibotenate into the striatum, but not into the substantia nigra, decrease these two opioid peptides in the substantia nigra on the side ipsilateral to the lesion, failing to modify the alpha-Neo levels in the ventral tegmental area. Bilateral electrolytic lesion of the habenula augmented alpha-Neo content in the substantia nigra and ventral tegmental area at 8-30 days postlesion without affecting the nigral Dyn A(1-8). These results add further support to the view that alpha-Neo- and Dyn A(1-8)-containing neurons projecting to the substantia nigra originate in the striatum and descend through striatonigral pathways. The present data provide evidence that the habenula may participate in the regulation of the activity of alpha-Neo-immunoreactive neurons in the substantia nigra and ventral tegmental area. 相似文献
7.
Schindowski K von Bohlen und Halbach O Strelau J Ridder DA Herrmann O Schober A Schwaninger M Unsicker K 《Cell and tissue research》2011,343(2):399-409
GDF-15 is a novel distant member of the TGF-β superfamily and is widely distributed in the brain and peripheral nervous system.
We have previously reported that GDF-15 is a potent neurotrophic factor for lesioned dopaminergic neurons in the substantia
nigra, and that GDF-15-deficient mice show progressive postnatal losses of motor and sensory neurons. We have now investigated
the regulation of GDF-15 mRNA and immunoreactivity in the murine hippocampal formation and selected cortical areas following
an ischemic lesion by occlusion of the middle cerebral artery (MCAO). MCAO prominently upregulates GDF-15 mRNA in the hippocampus
and parietal cortex at 3 h and 24 h after lesion. GDF-15 immunoreactivity, which is hardly detectable in the unlesioned brain,
is drastically upregulated in neurons identified by double-staining with NeuN. NeuN staining reveals that most, if not all,
neurons in the granular layer of the dentate gyrus and pyramidal layers of the cornu ammonis become GDF-15-immunoreactive.
Moderate induction of GDF-15 immunoreactivity has been observed in a small number of microglial cells identified by labeling
with tomato lectin, whereas astroglial cells remain GDF-15-negative after MCAO. Comparative analysis of the size of the infarcted
area after MCAO in GDF-15 wild-type and knockout mice has failed to reveal significant differences. Together, our data substantiate
the notion that GDF-15 is prominently upregulated in the lesioned brain and might be involved in orchestrating post-lesional
responses other than the trophic support of neurons. 相似文献
8.
Human FGF1 promoter is active in ependymal cells and dopaminergic neurons in the brains of F1B‐GFP transgenic mice
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Mei‐Shu Chen Hua‐Kuo Lin Hsun Chiu Don‐Ching Lee Yu‐Fen Chung Ing‐Ming Chiu 《Developmental neurobiology》2015,75(3):232-248
FGF1 is involved in multiple biological functions and exhibits the importance in neuroprotective effects. Our previous studies indicated that, in human brain and retina, the FGF1B promoter controlled the expression of FGF1. However, the exact function and regulation of FGF1 in brain is still unclear. Here, we generated F1B‐GFP transgenic mice that expressed the GFP reporter gene under the control of human FGF1B promoter (?540 to +31). Using the fresh brain sections of F1B‐GFP transgenic mice, we found that the F1B‐GFP cells expressed strong fluorescent signals in the ventricular system throughout the brain. The results of immunohistochemistry further showed that two distinct populations of F1B‐GFP+ cells existed in the brains of F1B‐GFP transgenic mice. We demonstrated that one population of F1B‐GFP+ cells was ependymal cells, which distributed along the entire ventricles, and the second population of F1B‐GFP+ cells was neuronal cells that projected their long processes into multiple directions in specific areas of the brain. The double labeling of F1B‐GFP+ cells and tyrosine hydroxylase indicated that a subpopulation of F1B‐GFP+‐neuronal cells was dopaminergic neurons. Importantly, these F1B‐GFP+/TH+ cells were distributed in the main dopaminergic neuronal groups including hypothalamus, ventral tegmental area, and raphe nuclei. These results suggested that human FGF1B promoter was active in ependymal cells, neurons, and a portion of dopaminergic neurons. Thus, the F1B‐GFP transgenic mice provide an animal model not only for studying FGF1 gene expression in vivo but also for understanding the role of FGF1 contribution in neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. © 2014 Wiley Periodicals, Inc. Develop Neurobiol 75: 232–248, 2015 相似文献
9.
Nigral and Striatal Comparative Study of the Neurotoxic Action of 1-Methyl-4-Phenylpyridinium Ion: Involvement of Dopamine Uptake System 总被引:2,自引:1,他引:1
Abstract: Microdialysis was used in a comparative study of the neurotoxic action of MPP+ in the absence or presence of nomifensine (20 µM) in the striatum and substantia nigra. Three different concentrations of MPP+ (1, 2.5, and 5 mM) were perfused for 15 min at 24 (day 1) and 48 h (day 2) after surgery. The dopamine basal value in the striatum was ~17 fmol/min. Nomifensine (20 µM) stimulated dopamine release to ~170 fmol/min. The increase of dopamine extracellular output in the striatum after MPP+ perfusion on day 1 was independent of the concentration of MPP+ perfused and of the absence or presence of nomifensine (20 µM), being ~2,500 fmol/min. The dopamine basal value in the substantia nigra was below the detection limit of our HPLC equipment. Nomifensine (20 µM) stimulated dopamine release to ~6.3 fmol/min. The increase of dopamine extracellular output in the substantia nigra was MPP+ dose-dependent (1 mM, 75 fmol/min; 2.5 mM, 150 fmol/min; and 5 mM, 250 fmol/min) and independent of the presence or absence of nomifensine. On day 2, the presence of nomifensine on day 1 produced a total protection against MPP+ (1 mM) perfusion in the striatum, which was not observed against MPP+ (5 mM). MPP+ (1 mM) did not produce any neurotoxic action in the substantia in the absence or presence of nomifensine. The MPP+ (2.5 mM) effect on dopamine extracellular output in the absence of nomifensine (20 µM) in the substantia nigra on day 2 was similar to that of MPP+ (1 mM) in the striatum. The presence of nomifensine (20 µM) partially prevented the neurotoxic effect of MPP+ (2.5 mM) on dopaminergic cell bodies/dendrites in the substantia nigra. The MPP+ (5 mM) effect on dopamine extracellular output was similar in both structures studied in the absence or presence of nomifensine on day 2. These results suggest that terminals in the striatum are more sensitive to the neurotoxicity of MPP+ than cell bodies/dendrites in the substantia nigra. 相似文献
10.
Yun-Lian Lin Huey-Jen Tsay Tzu-Hsuan Lai Tsai-Teng Tzeng Young-Ji Shiao 《Journal of biomedical science》2015,22(1)
Background
Parkinson’s disease is the second most common neurodegenerative disorders after Alzheimer’s disease. The main cause of the disease is the massive degeneration of dopaminergic neurons in the substantia nigra. Neuronal apoptosis and neuroinflammation are thought to be the key contributors to the neuronal degeneration.Results
Both CATH.a cells and ICR mice were treated with 1-methyl-4-phenylpyridin (MPP+) to induce neurotoxicity in vitro and in vivo. Western blotting and immunohistochemistry were also used to analyse neurotoxicity, neuroinflammation and aberrant neurogenesis in vivo. The experiment in CATH.a cells showed that the treatment of MPP+ impaired intake of cell membrane and activated caspase system, suggesting that the neurotoxic mechanisms of MPP+ might include both necrosis and apoptosis. Pretreatment of lithospermic acid might prevent these toxicities. Lithospermic acid possesses specific inhibitory effect on caspase 3. In mitochondria, MPP+ caused mitochondrial depolarization and induced endoplasmic reticulum stress via increasing expression of chaperone protein, GRP-78. All the effects mentioned above were reduced by lithospermic acid. In animal model, the immunohistochemistry of mice brain sections revealed that MPP+ decreased the amount of dopaminergic neurons, enhanced microglia activation, promoted astrogliosis in both substantia nigra and hippocampus, and MPP+ provoked the aberrant neurogenesis in hippocampus. Lithospermic acid significantly attenuates all of these effects induced by MPP+.Conclusions
Lithospermic acid is a potential candidate drug for the novel therapeutic intervention on Parkinson’s disease. 相似文献11.
Human umbilical cord blood derived CD34+ stem cells are reported to mediate therapeutic effects in stroke animal models. Estrogen was known to protect against ischemic injury. The present study wished to investigate whether the protective effect of CD34+ cells against ischemic injury can be reinforced with complemental estradiol treatment in female ovariectomized rat and its possible mechanism. Experiment 1 was to determine the best optimal timing of CD34+ cell treatment for the neuroprotective effect after 60-min middle cerebral artery occlusion (MCAO). Experiment 2 was to evaluate the adjuvant effect of 17β-estradiol on CD34+ cell neuroprotection after MCAO. Experiment 1 showed intravenous infusion with CD34+ cells before MCAO (pre-treatment) caused less infarction size than those infused after MCAO (post-treatment) on 7T magnetic resonance T2-weighted images. Experiment 2 revealed infarction size was most significantly reduced after CD34+ + estradiol pre-treatment. When compared with no treatment group, CD34+ + estradiol pre-treatment showed significantly less ADC reduction at 2 h and 2 d, less CBF reduction at 2 h and less hyperperfusion at 2 d. The immunoreactivity of c-Fos, c-Jun and GFAP was attenuated, and BDNF showed significant recovery from 2 h to 2 d after MCAO, especially after CD34+ + estradiol pre-treatment. The present study suggests pre-treatment with CD34+ cells with complemental estradiol can be most protective against ischemic injury, which may act through stabilization of cerebral hemodynamics and normalization of the expressions of immediate early genes and BDNF. 相似文献
12.
Shengli Zhao Yang Zhou Jimmy Gross Pei Miao Li Qiu Dongqing Wang Qian Chen Guoping Feng 《PloS one》2010,5(9)
Neurogenesis in the adult hippocampus is an important form of structural plasticity in the brain. Here we report a line of BAC transgenic mice (GAD67-GFP mice) that selectively and transitorily express GFP in newborn dentate granule cells of the adult hippocampus. These GFP+ cells show a high degree of colocalization with BrdU-labeled nuclei one week after BrdU injection and express the newborn neuron marker doublecortin and PSA-NCAM. Compared to mature dentate granule cells, these newborn neurons show immature morphological features: dendritic beading, fewer dendritic branches and spines. These GFP+ newborn neurons also show immature electrophysiological properties: higher input resistance, more depolarized resting membrane potentials, small and non-typical action potentials. The bright labeling of newborn neurons with GFP makes it possible to visualize the details of dendrites, which reach the outer edge of the molecular layer, and their axon (mossy fiber) terminals, which project to the CA3 region where they form synaptic boutons. GFP expression covers the whole developmental stage of newborn neurons, beginning within the first week of cell division and disappearing as newborn neurons mature, about 4 weeks postmitotic. Thus, the GAD67-GFP transgenic mice provide a useful genetic tool for studying the development and regulation of newborn dentate granule cells. 相似文献
13.
Juan Juan Ji Lianwan Chen Xuezhi Duan Xueqin Song Wenting Su Peng Zhang Li Li Shuyun Bai Yingchun Sun Nobuya Inagaki 《PloS one》2012,7(12)
Whether large conductance Ca2+-activated potassium (BK) channels are present in the substantia nigra pars reticulata (SNr) is a matter of debate. Using the patch-clamp technique, we examined the functional expression of BK channels in neurons of the SNr and showed that the channels were activated or inhibited by internal high-energy phosphates (IHEPs) at positive and negative membrane potentials, respectively. SNr neurons showed membrane potential hyperpolarization under glucose-deprivation conditions which was attenuated by paxilline, a specific BK channel blocker. In addition, Fluo-3 fluorescence recording detected an increase in the level of internal free calcium ([Ca2+]i) during ischemic hyperpolarization. These results confirm that BK channels are present in SNr neurons and indicate that their unique IHEP sensitivity is requisite in neuronal ischemic responses. Bearing in mind that the KATP channel blocker tolbutamide also attenuated the hyperpolarization, we suggest that BK channels may play a protective role in the basal ganglia by modulating the excitability of SNr neurons along with KATP channels under ischemic stresses. 相似文献
14.
Increased acoplasmic transport of H3-dopamine in nigro-neostriatal neurons after reserpine 总被引:1,自引:0,他引:1
Recent evidence suggests that dopamine can undergo axoplasmic transport in nigro-neostriatal neurons by binding to amine storage granules. In the present experiments it was demonstrated that reserpine pretreatment (10 mg/kg) 24 hours before stereotaxic injections of 3H-DOPA or 3H-dopamine into the substantia nigra increases the amount of 3H-dopamine transported to the neostriatum by about 300 percent. The activity recovered from the substantia nigra was significantly reduced by reserpine pretreatment however. Stereotaxic injection of 14C-leucine into the substantia nigra indicated that neither fast nor slow axoplasmic transport of protein was influenced by reserpine pretreatment in these same neurons. The increased transport of dopamine appears therefore to be due to a relatively selective action of reserpine. The results suggest that reserpine either (i) increases the binding of dopamine to newly synthesized amine storage granules, (ii) increases the number of newly synthesized amine storage granules, or (iii) accelerates the rate of transport of amine storage granules. In addition, the results support the view that reserpine can increase the membrane permeability of adrenergic neurons to the outward movement of catecholamines. 相似文献
15.
Ahmadi FA Grammatopoulos TN Poczobutt AM Jones SM Snell LD Das M Zawada WM 《Neurochemical research》2008,33(5):886-901
Among various types of neurons affected in Parkinson’s disease, dopamine (DA) neurons of the substantia nigra undergo the
most pronounced degeneration. Products of DA oxidation and consequent cellular damage have been hypothesized to contribute
to neuronal death. To examine whether elevated intracellular DA will selectively predispose the dopaminergic subpopulation
of nigral neurons to damage by an oxidative insult, we first cultured rat primary mesencephalic cells in the presence of rotenone
to elevate reactive oxygen species. Although MAP2+ neurons were more sensitive to rotenone-induced toxicity than type 1 astrocytes, rotenone affected equally both DA (TH+) neurons and MAP2+ neurons. In contrast, when intracellular DA concentration was elevated, DA neurons became selectively sensitized to rotenone.
Raising intracellular DA levels in primary DA neurons resulted in dopaminergic neuron death in the presence of subtoxic concentrations
of rotenone. Furthermore, mitochondrial superoxide dismutase mimetic, manganese (III) meso-tetrakis (4-benzoic acid) porphyrin, blocked activation of caspase-3, and consequent cell death. Our results demonstrate
that an inhibitor of mitochondrial complex I and increased cytosolic DA may cooperatively lead to conditions of elevated oxidative
stress and thereby promote selective demise of dopaminergic neurons. 相似文献
16.
Atsushi Takeda Jinko Sawashita Sachiyo Takefuta Shoji Okada 《Biological trace element research》1998,61(1):71-78
To study the relationship between tissue accumulation of Zinc (Zn) and neurodegeneration in the nigrostriatal dopaminergic
pathway,65Zn distribution in this pathway was examined after unilateral injection of 6-hydroxydopamine (6-OHDA) into the substantia
nigra of rats. When65ZnCl2 was intravenously injected 4 days after treatment with 6-OHDA,65Zn was concentrated in the ipsilateral substantia nigra 6 days after65Zn injection. On the other hand, 19 d after treatment with 6-OHDA,65Zn distribution in the ipsilateral substantia nigra was decreased to the level of the contralateral one. When NH4
99TcO4, which cannot go through the blood-brain barrier, was injected into rats 4 d after treatment with 6-OHDA,99Tc was concentrated in the ipsilateral substantia nigra 30 min after99Tc injection, but no longer detectable 6 d after injection. These results suggest that Zn is necessary for a repair process
called replacement gliosis after the death of neurons and that excess Zn does not accumulate in the lesion after completion
of the gliosis. 相似文献
17.
Eun Jeong Sohn Min Jea Shin Dae Won Kim Eun Hee Ahn Hyo Sang Jo Duk-Soo Kim Sung-Woo Cho Kyu Hyung Han Jinseu Park Won Sik Eum Hyun Sook Hwang Soo Young Choi 《Molecules and cells》2014,37(3):226-233
Excessive reactive oxygen species (ROS) generated from abnormal cellular process lead to various human diseases such as inflammation, ischemia, and Parkinson’s disease (PD). Sensitive to apoptosis gene (SAG), a RING-FINGER protein, has anti-apoptotic activity and anti-oxidant activity. In this study, we investigate whether Tat-SAG, fused with a Tat domain, could protect SH-SY5Y neuroblastoma cells against 1-methyl-4-phenylpyridinium (MPP+) and dopaminergic (DA) neurons in the substantia nigra (SN) against 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) toxicity. Western blot and immunohistochemical analysis showed that, unlike SAG, Tat-SAG transduced efficiently into SH-SY5Y cells and into the brain, respectively. Tat-SAG remarkably suppressed ROS generation, DNA damage, and the progression of apoptosis, caused by MPP+ in SH-SY5Y cells. Also, immunohistochemical data using a tyrosine hydroxylase antibody and cresyl violet staining demonstrated that Tat-SAG obviously protected DA neurons in the SN against MPTP toxicity in a PD mouse model. Tat-SAG-treated mice showed significant enhanced motor activities, compared to SAG- or Tat-treated mice. Therefore, our results suggest that Tat-SAG has potential as a therapeutic agent against ROS-related diseases such as PD. 相似文献
18.
Margaret E. Rice Jyoti C. Patel 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2015,370(1672)
Dopamine (DA) is a key transmitter in motor, reward and cogitative pathways, with DA dysfunction implicated in disorders including Parkinson''s disease and addiction. Located in midbrain, DA neurons of the substantia nigra pars compacta project via the medial forebrain bundle to the dorsal striatum (caudate putamen), and DA neurons in the adjacent ventral tegmental area project to the ventral striatum (nucleus accumbens) and prefrontal cortex. In addition to classical vesicular release from axons, midbrain DA neurons exhibit DA release from their cell bodies and dendrites. Somatodendritic DA release leads to activation of D2 DA autoreceptors on DA neurons that inhibit their firing via G-protein-coupled inwardly rectifying K+ channels. This helps determine patterns of DA signalling at distant axonal release sites. Somatodendritically released DA also acts via volume transmission to extrasynaptic receptors that modulate local transmitter release and neuronal activity in the midbrain. Thus, somatodendritic release is a pivotal intrinsic feature of DA neurons that must be well defined in order to fully understand the physiology and pathophysiology of DA pathways. Here, we review recent mechanistic aspects of somatodendritic DA release, with particular emphasis on the Ca2+ dependence of release and the potential role of exocytotic proteins. 相似文献
19.
Anamitra Ghosh Hariharan Saminathan Arthi Kanthasamy Vellareddy Anantharam Huajun Jin Gautam Sondarva Dilshan S. Harischandra Ziqing Qian Ajay Rana Anumantha G. Kanthasamy 《The Journal of biological chemistry》2013,288(30):21955-21971
Parkinson disease (PD) is a chronic neurodegenerative disease characterized by a slow and progressive degeneration of dopaminergic neurons in substantia nigra. The pathophysiological mechanisms underlying PD remain unclear. Pin1, a major peptidyl-prolyl isomerase, has recently been associated with certain diseases. Notably, Ryo et al. (Ryo, A., Togo, T., Nakai, T., Hirai, A., Nishi, M., Yamaguchi, A., Suzuki, K., Hirayasu, Y., Kobayashi, H., Perrem, K., Liou, Y. C., and Aoki, I. (2006) J. Biol. Chem. 281, 4117–4125) implicated Pin1 in PD pathology. Therefore, we sought to systematically characterize the role of Pin1 in PD using cell culture and animal models. To our surprise we observed a dramatic up-regulation of Pin1 mRNA and protein levels in dopaminergic MN9D neuronal cells treated with the parkinsonian toxicant 1-methyl-4-phenylpyridinium (MPP+) as well as in the substantia nigra of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. Notably, a marked expression of Pin1 was also observed in the substantia nigra of human PD brains along with a high co-localization of Pin1 within dopaminergic neurons. In functional studies, siRNA-mediated knockdown of Pin1 almost completely prevented MPP+-induced caspase-3 activation and DNA fragmentation, indicating that Pin1 plays a proapoptotic role. Interestingly, multiple pharmacological Pin1 inhibitors, including juglone, attenuated MPP+-induced Pin1 up-regulation, α-synuclein aggregation, caspase-3 activation, and cell death. Furthermore, juglone treatment in the MPTP mouse model of PD suppressed Pin1 levels and improved locomotor deficits, dopamine depletion, and nigral dopaminergic neuronal loss. Collectively, our findings demonstrate for the first time that Pin1 is up-regulated in PD and has a pathophysiological role in the nigrostriatal dopaminergic system and suggest that modulation of Pin1 levels may be a useful translational therapeutic strategy in PD. 相似文献
20.