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Query: UNIPROT:P06889 (Mol)
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Neuronal peptides exert neurohormonal and neurotransmitter (neuromodulator) functions in the central nervous system (CNS). Besides these functions, a group of neuropeptides may have a capacity to create cell proliferation, growth, and survival. Axotomy induces transient (1-21 d) upregulation of synthesis and gene expression of neuropeptides, such as galanin, corticotropin releasing factor, dynorphin, calcitonin gene-related peptide, vasoactive intestinal polypeptide, cholecystokinin, angiotensin II, and neuropeptide Y. These neuropeptides are colocalized with "classic" neurotransmitters (acetylcholine, aspartate, glutamate) or neurohormones (vasopressin, oxytocin) that are downregulated by axotomy in the same neuronal cells. It is more likely that neuronal cells, in response to axotomy, increase expression of neuropeptides that promote their survival and regeneration, and may downregulate substances related to their transmitter or secretory activities.
Mol Neurobiol
PMID:Neuropeptide messenger plasticity in the CNS neurons following axotomy. 757 12

Neuronal activity of the suprachiasmatic nucleus (SCN) is known to be regulated by two major extrinsic factors conveyed by three anatomically distinct pathways to the SCN: photic stimulus by the direct retinohypothalamic tract (RHT) and the indirect geniculohypothalamic tract (GHT), and information from the brainstem by ascending forebrain serotonergic (5-hydroxytryptamine: 5-HT) tract. It has been shown that VIP mRNA level in neurons of the SCN is altered by external light, but remains stable in constant darkness. In the present study, by using the in situ hybridization technique combined with computer-assisted image analysis, we examined VIP mRNA expression in the SCN of rats in which the two major factors were eliminated, i.e. photic stimulus by exposing animals in total darkness and 5-HT transmission by three-day successive administration of p-chlorophenyl-alanine methylester (an inhibitor of tryptophan hydroxylase, 200 mg/kg, daily). In saline-treated controls, VIP mRNA levels remained almost constant throughout the day. In contrast, in PCPA-treated rats, a significant rhythm of VIP mRNA was observed with a peak at CT 4 and a trough at CT 20. These observations suggest that the removal of photic and 5-HT influence induces VIP mRNA rhythm in the SCN, indicating that VIP mRNA is controlled not only by photic information but also by the circadian clock.
Brain Res Mol Brain Res 1995 Apr
PMID:Circadian change of VIP mRNA in the rat suprachiasmatic nucleus following p-chlorophenylalanine (PCPA) treatment in constant darkness. 760 23

Brain halves were collected at various time points from 21-day-old Wistar rats exposed to either a short or prolonged period of inhalational hypoxia following unilateral carotid ligation post-insult. Neuronal loss was restricted to the side of the carotid ligation. Northern blot analysis was performed for IGFBP-2 mRNA. The prolonged hypoxia decreased the expression of IGFBP-2 five hours post insult, whereas the shorter insult level showed an (P < 0.05) increase above control. In both groups IGFBP-2 mRNA increased to peak 3-5 days post insult. After a decline at day 6, expression was again high 7-10 days after HI. In the short hypoxia group, where there was little neuronal loss, the expression of IGFBP-2 in both hemispheres followed the same pattern over time. However prolonged hypoxia induced higher IGFBP-2 expression in the ligated hemisphere where there was extensive neuronal loss. At day 5 post-insult 5/9 rats showed an additional, slightly smaller (1.4 kb vs 1.7 kb) second transcript. The different pattern of expression associated with different degrees of injury suggest that IGFBP-2 is involved in the post asphyxial response. Hypoxia itself leads to alterations in IGFBP-2 expression. Greater expression is associated with neuronal loss. These observations suggest that the IGF system contributes to neuronal rescue and/or brain repair processes.
Brain Res Mol Brain Res 1993 Mar
PMID:Hypoxia and hypoxia/ischemia affect the expression of insulin-like growth factor binding protein 2 in the developing rat brain. 768 64

Neuronal differentiation is accompanied by extensive reorganization of the cytoskeleton to initiate the extension of neuritic processes. We have used the rat PC12 pheochromocytoma cell line to examine the role of protein tyrosine kinase activity in the induction of these events. Immunoblotting with phosphotyrosine antibodies revealed that tyrosine phosphorylation of alpha-tubulin in PC12 cells occurred within 10 min of nerve growth factor (NGF) treatment. Tyrosine phosphorylation of alpha-tubulin also occurred on induction of pp60v-src expression in a PC12 cell line (PC12-B9) harboring an inducible v-src gene under transcriptional control of the mouse metallothionine I gene promoter. Two tyrosine phosphorylated proteins in NGF- and pp60v-src induced PC12 cells were identified as alpha-tubulin isoforms by comigration with alpha-tubulin on two-dimensional gel electrophoresis, and by immunoprecipitation with phosphotyrosine antibodies followed by immunoblotting with a monoclonal antibody specific for alpha-tubulin. These results demonstrate that alpha-tubulin is an in vivo tyrosine kinase substrate, which is phosphorylated as an early event in the neuronal differentiation pathway of PC12 cells in response to NGF or pp60v-src. Tyrosine phosphorylation of alpha-tubulin could conceivably alter microtubule dynamics during induction of neurite extension.
J Mol Neurosci 1993
PMID:Tyrosine phosphorylation of alpha-tubulin is an early response to NGF and pp60v-src in PC12 cells. 769 12

Neuronal nicotinic acetylcholine receptor subunits alpha 3 (PCA48E) and beta 4S (ZPC13) were expressed in human embryonic kidney (HEK)-293 cells by calcium phosphate transfection. In the presence of atropine, acetylcholine (ACh) induced fast activating currents which exhibited desensitization and inward rectification. The EC50 for ACh was 202 +/- 32 microM with a Hill coefficient of 1.9 +/- 0.4. The rank order of nicotinic agonist potency was 1,1-dimethyl-4-phenylpiperozinium (DMPP) > cytisine = nicotine approximately equal to ACh. The maximal response elicited by DMPP was substantially less than that elicited by other agonists, suggesting that DMPP is a partial agonist. ACh (500 microM) responses were very effectively blocked by equimolar concentrations (100 microM) of the ganglionic antagonists d-tubocurarine, mecamylamine and hexamethonium. Equal concentrations of the potent muscle receptor antagonist decamethonium and the competitive antagonist dihydro-beta-erythroidine were much less effective. alpha bungaro-toxin (1 microM) had little effect on ACh-induced responses. This physiological and pharmacological profile is consistent with a ganglionic nicotinic response.
Brain Res Mol Brain Res 1995 Jan
PMID:Pharmacological and physiological properties of a putative ganglionic nicotinic receptor, alpha 3 beta 4, expressed in transfected eucaryotic cells. 770 62

Neuronal acetylcholine receptors (AChRs) that bind alpha-bungarotoxin (alpha Bgt) (alpha Bgt-AChRs) have previously been found to contain at least one of the alpha 7-alpha 9 gene products. No other gene products of the 11 neuronal AChR genes cloned to date from rat and/or chick have been identified in such receptors. Chick ciliary ganglia have about 20 fmol of alpha Bgt-AChRs that contain alpha 7 subunits and 5 fmol of synaptic-type AChRs that bind the monoclonal antibody (mAb) 35 and collectively contain alpha 3, beta 4, alpha 5, and, to a lesser extent, beta 2 subunits. Using a sensitive solid-phase immunoprecipitation assay, we show here that ciliary ganglia have about 1 fmol of novel putative AChRs that bind both alpha Bgt and mAb 35 but appear to lack all of the known neuronal AChR gene products in ciliary ganglia, including alpha 3, alpha 5, alpha 7, beta 2, and beta 4. The putative receptors are also unlikely to contain either alpha 8 or alpha 9 gene products, because of the known expression patterns of these gene products. Nonetheless, the component sediments at 10 S, as expected for neuronal AChRs, and has a nicotinic pharmacology similar but not identical to that of alpha 7-containing alpha Bgt-AChRs. The AChR alpha 1 gene product expressed in muscle is known to bind both alpha Bgt and mAb 35, and we show here that ciliary ganglia contain small amounts of alpha 1 transcript. The putative ciliary ganglion AChR defined by joint alpha Bgt and mAb 35 binding, however, does not appear to contain alpha 1 subunits. A similar component binding both mAb 35 and alpha Bgt can be detected in sympathetic ganglia and dorsal root ganglia but not in brain, spinal cord, or retina. The developmental time course of the component in ciliary ganglia is comparable to that of the alpha 7-containing alpha Bgt-AChRs. If the component is a functional AChR on ciliary ganglion neurons, as seems likely, it would represent the fourth AChR subtype produced by this population of cells. Our inability to identify subunits comprising the putative receptors raises the possibility that additional AChR genes remain to be cloned.
Mol Pharmacol 1995 Apr
PMID:Novel subpopulation of neuronal acetylcholine receptors among those binding alpha-bungarotoxin. 772 32

The functional effects of G protein-linked glutamate receptor activation have been studied in mouse mesencephalic neurons in vitro. We have been able to identify two receptor classes, one linked to phosphoinositide hydrolysis and another that inhibits adenylate cyclase. The agonist (1S,3R)-aminocyclopentane-1,3-dicarboxylate (ACPD) affected the two responses with similar potency (EC50 = 2 and 7 microM, respectively). In contrast, (2S,3S,4S)-alpha-(carboxycyclopropyl)glycine selectively decreased adenylate cyclase activity (EC50 = 150 nM), without interfering with the phosphoinositide pathway. Activation of ion channel-linked glutamate receptors in mesencephalic neurons leads to cGMP formation. In this study, we demonstrate that cell pretreatment with ACPD or (2S,3S,4S)-alpha-(carboxycyclopropyl)glycine prevented, in a dose-dependent fashion, N-methyl-D-aspartate (NMDA)-induced cGMP formation but not the kainate-stimulated response. The pharmacological profile suggests that receptors that are negatively coupled to adenylate cyclase are responsible for this effect. Coexposure of neurons to ACPD and Ba2+, a K+ channel blocker, counteracted the ACPD-induced blockade of NMDA receptors, suggesting that activation of K+ conductances could be involved in the post-transduction events triggered by metabotropic receptors in the mesencephalon. Neuronal treatment with NMDA for 10 min caused a reduction in mitochondrial activity. Direct inhibition of nitric oxide synthase with the inhibitor NG-nitro-L-arginine or removal of extracellular nitric oxide with reduced hemoglobin did not prevent this metabolic impairment, thus excluding a role for nitric oxide in this test for excitotoxicity. On the contrary, the mitochondrial function was maintained when neurons exposed to NMDA were preincubated with metabotropic receptor agonists. To summarize, our results suggest that metabotropic receptors that are negatively coupled to adenylate cyclase exert modulatory control specifically on NMDA receptor activity. This event could also contribute to the reduction of neurotoxic effects due to NMDA receptor hyperactivity.
Mol Pharmacol 1995 May
PMID:Metabotropic glutamate receptors negatively coupled to adenylate cyclase inhibit N-methyl-D-aspartate receptor activity and prevent neurotoxicity in mesencephalic neurons in vitro. 774 73

Dopaminergic (DA) cells of the substantia nigra pars compacta (SNC) and the ventral tegmental area (VTA) display differences in their topography, biochemistry and susceptibility to pathological processes. Neuronal dopamine concentration is regulated in large part by tyrosine hydroxylase (TH), the rate-limiting enzyme of dopamine synthesis, and by the dopamine reuptake system. In the present study, TH protein, TH mRNA and dopamine membrane transporter (DAT) mRNA were quantified at cellular level in 4 arbitrary subregions of the rat ventral mesencephalon (lateral, middle, medial SNC and VTA), using in situ hybridization and immunoautoradiography. The distribution of labelling for TH protein and TH mRNA was almost superimposable and close to that of DAT mRNA in mesencephalic neurons. Lower values of cellular expression in TH protein, TH mRNA and DAT mRNA were observed in the lateral part of the SNC compared to the other subregions. TH and DAT expression were correlated in SNC but not in VTA. Indeed DA cells in this region expressed low levels of DAT mRNA in comparison to the middle and medial SNC. These results suggest a heterogeneity of DA metabolism among populations of mesencephalic cells. The relative lower expression of the DAT gene in VTA neurons suggests a less efficient dopamine reuptake capacity, which may partly account for the relative sparing of the mesolimbic system reported in Parkinson's disease and MPTP-treated animals.
Brain Res Mol Brain Res 1994 Mar
PMID:Differential expression of tyrosine hydroxylase and membrane dopamine transporter genes in subpopulations of dopaminergic neurons of the rat mesencephalon. 791 4

Reactive gliosis is part of the response of central nervous system to injury and neurodegeneration. Cellular components of the reactive gliosis have the capability to synthesize neurotrophic factors, and thus are capable of affecting the fate of neuronal populations in the injured tissue. In this study, we explored the putative involvement of reactive glia-derived neurotrophins in sustaining the axonal projections of target-deprived neurons. Neuronal targets of the dorsal column nuclei neurons were suppressed through excitotoxic lesion of the ventrobasal complex of the rat thalamus (VB). Despite the development of reactive gliosis, neither up-regulation of NGF, nor BDNF or NT3 mRNA could be detected by solution hybridization in the lesioned site at all times tested. In contrast, expression of the LNGFR gene increased progressively up to 90 days post-lesion. Immunocytochemical studies localized the LNGFR protein in a subset of small cells with ramified processes resembling microglia at 7 and 20 days post-lesion. At longer times, double immunolabelling studies revealed that a substantial part of LNGFR-immunoreactive cells filling the area of neuronal loss were neither microglial cells nor astrocytes although presence of LNGFR in a subset of microglial cells could not be excluded. Previous ultrastructural studies of the kainate-lesioned VB suggest that these LNGFR-immunoreactive cells correspond to oligodendrocytes and/or Schwann cells. At 2 months post-lesion, when LNGFR expression was maximal, increased levels of trkA mRNA were detected in the lesioned site. Immunocytochemical studies revealed the presence of numerous trkA-immunoreactive astrocytes. TrkB mRNA, encoding the full-length high-affinity receptor for BDNF, remained undetectable by non-isotopic in situ hybridization. In contrast to the lack of neurotrophin gene expression by glial components of the lesioned VB, dorsal column nuclei neurons contained NGF mRNA as revealed by in situ hybridization studies at 10 days--prior to enhanced LNGFR expression in the lesion--and 2 months post-lesion. In addition, the number and the staining intensity of NGF mRNA-positive neurons was increased in the target-deprived neurons, as compared with the contra-lateral nucleus projecting to intact targets. These results show that glial cells present in a reactive gliosis which develops in the kainic acid-lesioned thalamus, do not synthesize neurotrophins but instead produce high levels of both low- and high-affinity NGF receptors, LNGFR by Schwann cells/oligodendrocytes and possibly a subset of microglial cells, and trkA by reactive astrocytes.(ABSTRACT TRUNCATED AT 400 WORDS)
Brain Res Mol Brain Res 1994 Jul
PMID:Target-deprived CNS neurons express the NGF gene while reactive glia around their axonal terminals contain low and high affinity NGF receptors. 796 64

The transcription factor KROX-20, unlike many other immediate early genes, is not expressed in the rat hippocampus after bicuculline induced generalized seizures. Since limbic seizures are a more injurious stimulus, the KROX-20 expression profile was investigated in adult rats subjected to kainic acid induced limbic epilepsy at postictal intervals up to 48 h. Immunocytochemistry was performed using a specific polyclonal antiserum. In the hippocampus a sequential induction was observed with peak levels attained in dentate gyrus at 3 h, in CA1 at 8 h and in CA3 between 8 and 24 h, respectively. In contrast, no KROX-20 induction was found in hilus neurons. Prominent neuronal KROX-20 induction was also detected in other areas of the limbic system, in particular in amygdala and piriform cortex, as well as non-limbic regions such as neocortex and striatum. As is the case with KROX-20, heat shock protein (HSP) 70, a reliable marker for reversible neuronal injury, has a high induction threshold. Though not inducible in the hippocampus by generalized seizures, it is expressed after limbic epilepsy. Therefore, co-expression of KROX-20 and HSP70 was studied by a double labeling technique using a monoclonal antibody directed against the inducible form of HSP70. Neuronal subpopulations with perfect co-expression such as hippocampal CA1 neurons contrasted with others demonstrating partial co-induction (cortical neurons) or lack of co-expression (hilus cells), indicating that different stimuli trigger the activation of these two inducible genes.
Brain Res Mol Brain Res 1994 Jun
PMID:High induction threshold for transcription factor KROX-20 in the rat brain: partial co-expression with heat shock protein 70 following limbic seizures. 809 69


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