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1.
Opt Lett ; 45(5): 1204-1207, 2020 Mar 01.
Article in English | MEDLINE | ID: mdl-32108806

ABSTRACT

We report on the experimental observation of internally pumped parametric oscillation in a high-$\!Q$Q lithium niobate microresonator under conditions of natural phase matching. Specifically, launching near-infrared pump light around 1060 nm into a $ z $z-cut congruent lithium niobate microresonator, we observe the generation of optical sidebands around the input pump under conditions where second-harmonic generation is close to natural phase matching. We find that a wide range of different sideband frequency shifts can be generated by varying the experimental parameters. Under particular conditions, we observe the cascaded generation of several sidebands around the pump-the first steps of optical frequency comb generation via cavity-enhanced second-harmonic generation.

2.
J Neurosci ; 29(13): 4016-22, 2009 Apr 01.
Article in English | MEDLINE | ID: mdl-19339597

ABSTRACT

Although brain-derived neurotrophic factor (BDNF) has been shown to promote peripheral myelination during development and remyelination after injury, the precise mechanisms mediating this effect remain unknown. Here, we determine that BDNF promotes myelination of nerve growth factor-dependent neurons, an effect dependent on neuronal expression of the p75 neurotrophin receptor, whereas BDNF inhibits myelination of BDNF-dependent neurons via the full-length TrkB receptor. Thus, BDNF exerts contrasting effects on Schwann cell myelination, depending on the complement of BDNF receptors that are expressed by different subpopulations of dorsal root ganglion neurons. These results demonstrate that BDNF exerts contrasting modulatory roles in peripheral nervous system myelination, and that its mechanism of action is acutely regulated and specifically targeted to neurons.


Subject(s)
Brain-Derived Neurotrophic Factor/physiology , Ganglia, Spinal/cytology , Myelin Proteins/metabolism , Nerve Growth Factor/physiology , Neurons/physiology , Animals , Animals, Genetically Modified , Animals, Newborn , Brain-Derived Neurotrophic Factor/pharmacology , Carbazoles/pharmacology , Cells, Cultured , Coculture Techniques/methods , Enzyme Inhibitors/pharmacology , Gene Expression Regulation/drug effects , Humans , Indole Alkaloids/pharmacology , Mice , Myelin Basic Protein/metabolism , Myelin P0 Protein/metabolism , Myelin-Associated Glycoprotein/metabolism , Nerve Growth Factor/pharmacology , Nerve Tissue Proteins/genetics , Neurons/drug effects , Rats , Rats, Sprague-Dawley , Receptors, Growth Factor/genetics , Receptors, Nerve Growth Factor/genetics , Schwann Cells/drug effects , Tissue Culture Techniques , Transfection
3.
Int J Dev Neurosci ; 26(6): 625-34, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18499388

ABSTRACT

Nerve cells require trophic signals transmitted from the nerve terminal via the axon in order to survive and develop normally. As the axon may be more than a meter long, specialised mechanisms are needed to transmit these signals. This involves the retrograde axonal transport of signalling endosomes containing nerve growth factor (NGF) and other synaptically derived molecules. These are large, double membrane multivesicular bodies containing a mixture of all vesicle types seen in the nerve terminal. How this signalling endosome is formed and targeted for retrograde axonal transport, however, remains an open question. Here we show that members of the Rab family of proteins that are retrogradely transported indicate that the signalling endosome contains both early and recycling endosomes. In addition, we show that retrogradely transported labelled antibody to dopamine beta-hydroxylase, a marker for synaptic vesicles, co-localizes within the same signalling endosome as NGF. We further show that LC3, a marker for autophagosomes, is retrogradely transported and associates with retrogradely transported NGF. We propose that neurons have exploited the mechanism of autophagy to engulf a sample of the cytoplasmic contents of the nerve terminal to transport back to the cell body. This sample of cytoplasmic contents relays a reliable snapshot of the totality of signalling events occurring in the nerve terminal at that instant in time.


Subject(s)
Autophagy/physiology , Axonal Transport/physiology , Nerve Growth Factors/metabolism , Organelles/physiology , Animals , Biotinylation/methods , Dopamine beta-Hydroxylase/metabolism , Ligation/methods , Microscopy, Confocal , Nerve Tissue Proteins , Rats , Rats, Wistar , Receptor, trkA/metabolism , Receptors, Growth Factor , Receptors, Nerve Growth Factor/metabolism , Sciatic Nerve/physiology , Sciatic Nerve/ultrastructure , Time Factors , rab GTP-Binding Proteins/metabolism
4.
J Biol Chem ; 283(8): 4560-7, 2008 Feb 22.
Article in English | MEDLINE | ID: mdl-18096703

ABSTRACT

Relatively little is known about the in vivo functions of the alpha subunit of the heterotrimeric G protein Gz (Galphaz). Clues to one potential function recently emerged with the finding that activation of Galphaz inhibits glucose-stimulated insulin secretion in an insulinoma cell line (Kimple, M. E., Nixon, A. B., Kelly, P., Bailey, C. L., Young, K. H., Fields, T. A., and Casey, P. J. (2005) J. Biol. Chem. 280, 31708-31713). To extend this study in vivo, a Galphaz knock-out mouse model was utilized to determine whether Galphaz function plays a role in the inhibition of insulin secretion. No differences were discovered in the gross morphology of the pancreatic islets or in the islet DNA, protein, or insulin content between Galphaz-null and wild-type mice. There was also no difference between the insulin sensitivity of Galphaz-null mice and wild-type controls, as measured by insulin tolerance tests. Galphaz-null mice did, however, display increased plasma insulin concentrations and a corresponding increase in glucose clearance following intraperitoneal and oral glucose challenge as compared with wild-type controls. The increased plasma insulin observed in Galphaz-null mice is most likely a direct result of enhanced insulin secretion, since pancreatic islets isolated from Galphaz-null mice exhibited significantly higher glucose-stimulated insulin secretion than those of wild-type mice. Finally, the increased insulin secretion observed in Galphaz-null islets appears to be due to the relief of a tonic inhibition of adenylyl cyclase, as cAMP production was significantly increased in Galphaz-null islets in the absence of exogenous stimulation. These findings indicate that Galphaz may be a potential new target for therapeutics aimed at ameliorating beta-cell dysfunction in Type 2 diabetes.


Subject(s)
GTP-Binding Protein alpha Subunits/metabolism , Glucose/pharmacology , Insulin/metabolism , Islets of Langerhans/metabolism , Sweetening Agents/pharmacology , Adenylyl Cyclases/genetics , Adenylyl Cyclases/metabolism , Animals , Cyclic AMP/genetics , Cyclic AMP/metabolism , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , GTP-Binding Protein alpha Subunits/genetics , Glucose/metabolism , Insulin Resistance/genetics , Insulin Secretion , Islets of Langerhans/pathology , Mice , Mice, Inbred BALB C , Mice, Knockout , Sweetening Agents/metabolism
5.
Psychopharmacology (Berl) ; 195(2): 273-83, 2007 Dec.
Article in English | MEDLINE | ID: mdl-17684732

ABSTRACT

RATIONALE: G(z), a member of the G(i) G protein family, is involved in the coupling of dopaminergic and serotonergic receptors. In the present study, we investigated behaviour of mice deficient in the alpha subunit of G(z) and focused on pre-pulse inhibition (PPI) and anxiety-like responses and the role of serotonin-1A (5-HT(1A)) receptors. MATERIALS AND METHODS: We compared male and female wild-type and knock-out mice on either a C57Bl/6 or Balb/c background. We used automated startle boxes to assess startle and PPI and elevated plus maze to assess anxiety-like behaviours. RESULTS: Balb/c mice showed higher baseline PPI than C57Bl/6 mice, and there was no difference between the genotypes. The 5-HT(1A) receptor agonist, 8-hydroxy-di-propylaminotetralin (8-OH-DPAT), had no effect on PPI in C57Bl/6 mice but markedly increased PPI in Balb/c mice, with the effect being attenuated in Galpha(z) knock-outs. On the elevated plus maze, there was little effect of the knock-out or 8-OH-DPAT in C57Bl/6 mice, whereas in Balb/c mice, Galpha(z) knock-outs showed a phenotype of high levels of anxiety-like behaviour. 8-OH-DPAT was anxiogenic in Balb/c mice, but this effect was attenuated in Galpha(z) knock-outs. CONCLUSIONS: 5-HT(1A) receptors couple to G(z). In a strictly background strain-dependent manner, Galpha(z) knock-out mice display high levels of anxiety-like behaviour and are less sensitive to the action of 8-OH-DPAT. Balb/c mice show much more clear effects of the Galpha(z) knock-out than C57Bl/6 mice, which are often considered the standard background strain for genetic modifications. Therefore, our results suggest caution when studying the behavioural effects of genetic modifications only in C57Bl/6 mice.


Subject(s)
Anxiety/genetics , Exploratory Behavior/drug effects , GTP-Binding Protein alpha Subunits/physiology , Reflex, Startle/genetics , Serotonin 5-HT1 Receptor Agonists , 8-Hydroxy-2-(di-n-propylamino)tetralin/pharmacology , Analysis of Variance , Animals , Female , GTP-Binding Protein alpha Subunits/genetics , Genetic Predisposition to Disease , Male , Maze Learning/drug effects , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Receptor, Serotonin, 5-HT1A/genetics , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin Receptor Agonists/pharmacology , Sex Factors , Signal Transduction , Species Specificity
6.
Neuropharmacology ; 51(3): 597-605, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16814816

ABSTRACT

The receptors that couple to the G protein Gz in vivo are still relatively unknown. In this study, we investigated the effects of various dopamine receptor agonists in a mouse deficient in the alpha subunit of Gz. The dopamine D1-like receptor agonist SKF38393 stimulated comparable locomotor activity in both wildtype mice and mice lacking Galphaz. In contrast, the dopamine D2-like receptor agonist quinpirole suppressed locomotor activity in both groups of mice, but this suppression was significantly smaller in Galphaz knockout mice. Consistent with these behavioural observations, quinpirole inhibition of dopamine release in the forebrain nucleus accumbens evoked by electrical stimulation of dopamine axons was significantly attenuated in mice lacking Galphaz. In addition, hypothermia and adrenocorticotropic hormone release resulting from activation of dopamine D2-like receptors were also significantly reduced in Galphaz knockout mice. However, adrenocorticotropic hormone secretion induced by corticotrophin releasing hormone and the serotonin 1A receptor agonist 8-hydroxy-dipropylamino-tetralin were similar between wildtype and Galphaz knockout mice. Western blot analysis showed that the expression levels of Galphai, Galphao, Galphas, Galphaq and Gbeta were the same in the brains of mice of both genotypes. Overall, our data suggest that Gz proteins are functionally coupled to dopamine D2-like receptors in vivo.


Subject(s)
Behavior, Animal/physiology , GTP-Binding Protein alpha Subunits/physiology , Receptors, Dopamine D2/physiology , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology , 8-Hydroxy-2-(di-n-propylamino)tetralin/pharmacology , Adrenocorticotropic Hormone/blood , Animals , Behavior, Animal/drug effects , Blotting, Western/methods , Body Temperature/drug effects , Body Temperature/physiology , Dopamine/metabolism , Dopamine Agonists/pharmacology , GTP-Binding Protein alpha Subunits/deficiency , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor Activity/drug effects , Motor Activity/physiology , Nucleus Accumbens/drug effects , Quinpirole/pharmacology , Serotonin Receptor Agonists/pharmacology , Tetrahydronaphthalenes/pharmacology , Time Factors
7.
Neurochem Res ; 30(6-7): 703-12, 2005.
Article in English | MEDLINE | ID: mdl-16187207

ABSTRACT

In this study we describe a population of neurons in the adult rat trigeminal ganglion (TG) that express dopamine beta-hydroxylase (DBH) and tyrosine hydroxylase (TH), and transport anti-DBH from their terminals. We have used NGF and NT3 labeled with biotin and anti-p75NTR labeled with FITC to examine the transport of neurotrophins and their receptors by these cells. In both the superior cervical ganglion (SCG) and the TG all neurons that transported anti-DBH transported NGF. While 100% of the DBH positive neurons in the TG also transported NT3, approximately 25% of these neurons in the SCG failed to transport NT3. In the SCG virtually all the neurons transported anti-p75NTR with the neurotrophins while in the TG more than 25% of these neurons failed to transport anti-p75NTR with the neurotrophins. These findings suggest that DBH positive neurons in the TG depend upon target-derived NGF and NT3 for their noradrenergic phenotype.


Subject(s)
Antibodies/immunology , Axons , Dopamine beta-Hydroxylase/immunology , Trigeminal Ganglion/metabolism , Animals , Biological Transport , Immunohistochemistry , Nerve Growth Factor/metabolism , Neurons/enzymology , Rats , Receptor, Nerve Growth Factor/metabolism , Tyrosine 3-Monooxygenase/metabolism
8.
Neuroreport ; 16(9): 921-5, 2005 Jun 21.
Article in English | MEDLINE | ID: mdl-15931062

ABSTRACT

The serotonin-1A [5-hydroxytryptamine 1A (5HT1A)] receptor is important for emotional and homeostatic processes in the central nervous system. In the hippocampus, the 5HT1A receptor couples to inhibitory Gi/o proteins to decrease pyramidal cell excitability. Here we investigate the 5HT1A receptor in a mouse deficient in the alpha-subunit of Gz protein (Galphaz knock-out). Behavioural tests showed heightened anxiety and depression-like behaviour in the Galphaz knock-out mice. Whole-cell recording in CA1 pyramidal neurons showed a significantly greater 5HT1A receptor-mediated potassium current in Galphaz knock-out mice. The effect was independent of 5HT4 receptors as the slow after-hyperpolarization was unaffected and a slow depolarization was absent in the Galphaz knock-out mice. Other receptors linked to Gi/o proteins [gamma-aminobutyric acid type B receptor (GABAB), adenosine A1 and muscarinic acetylcholine receptors] were not affected in Galphaz knock-out mice. These results suggest that the 5HT1A receptor may be linked to Galphaz protein, as reported previously in cell culture but shown here in an intact neural network.


Subject(s)
GTP-Binding Protein alpha Subunits/deficiency , Hippocampus/metabolism , Receptor, Serotonin, 5-HT1A/physiology , Serotonin/physiology , Adenosine/pharmacology , Animals , Baclofen/pharmacology , Behavior, Animal/physiology , Blotting, Western/methods , Carbachol/pharmacology , Cholinergic Agonists/pharmacology , Drug Interactions , Electric Conductivity , Electric Stimulation/methods , Fluorescent Antibody Technique/methods , GABA Agonists/pharmacology , GTP-Binding Protein alpha Subunits/physiology , Hippocampus/cytology , Membrane Potentials/drug effects , Membrane Potentials/physiology , Membrane Potentials/radiation effects , Mice , Mice, Inbred C57BL , Mice, Knockout/physiology , Patch-Clamp Techniques/methods , Piperazines/pharmacology , Potassium/metabolism , Pyramidal Cells/drug effects , Pyramidal Cells/physiology , Pyridines/pharmacology , Serotonin Antagonists/pharmacology , Swimming/physiology
9.
Neuropharmacology ; 48(2): 274-82, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15695166

ABSTRACT

The blood-brain barrier acts as an interface between the brain and body through a combination of restrictive mechanisms and transport processes. Substances essential for brain function pass through the barrier either by passive diffusion or by active transport. We report here that [125I]-transforming growth factor-beta2 (TGF-beta2) passes through the blood-brain barrier and blood-nerve barriers, after intravenous, intraperitoneal or intramuscular injections. The entry of the [125I]-TGF-beta2 to the brain was rapid, saturable and inhibited by co-injection of unlabelled TGF-beta2. In contrast, co-injection of unlabelled TGF-beta2 increased the retention of [125I]-TGF-beta2 in the blood. The [125I]-TGF-beta2 transported into the brain was localised by autoradiography to the extracellular space, and was intact as judged by SDS-PAGE. The [125I]-TGF-beta2 was widely distributed throughout the brain, with the highest concentrations in the hypothalamus and nerves and the lowest in the cerebral hemispheres. The [125I]-TGF-beta2 had a half-life of 4 h in the brain. These results indicate that therapeutically relevant levels of TGF-beta2 reach the brain after peripheral administration of TGF-beta2.


Subject(s)
Blood-Brain Barrier/metabolism , Brain/metabolism , Transforming Growth Factor beta/metabolism , Animals , Blood-Brain Barrier/drug effects , Brain/drug effects , Female , Humans , Mice , Mice, Inbred BALB C , Protein Transport/physiology , Transforming Growth Factor beta/administration & dosage
10.
Neurosci Lett ; 361(1-3): 216-9, 2004 May 06.
Article in English | MEDLINE | ID: mdl-15135932

ABSTRACT

In anaesthetized cats, antibody microprobes were used to measure the release of immunoreactive substance P (irSP) in the lumbar dorsal horn during electrical stimulation of primary afferent fibres at intensities suprathreshold for unmyelinated fibres. Release of irSP was detected in the region of the superficial dorsal horn. This evoked release was not reduced by clonidine hydrochloride, administered intravenously or by superfusion of the dorsal cord surface. Microprobes inserted during cord superfusion with lignocaine hydrochloride detected less irSP along their entire length, including in the region of evoked release. The results suggest that the analgesic action of clonidine does not involve reduced release of SP from the central terminals of nociceptors in the spinal cord.


Subject(s)
Afferent Pathways/physiology , Clonidine/pharmacology , Nerve Fibers, Unmyelinated/physiology , Nociceptors/drug effects , Pain/drug therapy , Spinal Cord/drug effects , Substance P/metabolism , Analgesics/pharmacology , Animals , Cats , Dose-Response Relationship, Drug , Down-Regulation/drug effects , Down-Regulation/physiology , Electric Stimulation , Lidocaine/pharmacology , Nociceptors/metabolism , Pain/metabolism , Pain/physiopathology , Presynaptic Terminals/drug effects , Presynaptic Terminals/metabolism , Spinal Cord/metabolism , Synaptic Transmission/drug effects , Synaptic Transmission/physiology
11.
J Neurosci Res ; 72(2): 203-10, 2003 Apr 15.
Article in English | MEDLINE | ID: mdl-12671995

ABSTRACT

Retrograde axonal transport of neurotrophins from nerve terminal to cell body requires a number of key processes, including internalization of the receptor-neurotrophin complex into vesicles and formation of multivesicular bodies and their transport along the axon. Previous studies have shown that each of these processes can be regulated by kinases. In this study, we looked at the role of protein kinase C (PKC) in retrograde transport by injecting labeled neurotrophins together with relevant pharmacological agents into the eye and measuring the accumulation of radioactivity in the trigeminal and superior cervical ganglia. Inhibitors of PKC, Ro-31-8220 and rottlerin, did not affect the retrograde transport of nerve growth factor (NGF); however, phorbol ester activation of classical and novel PKCs blocked retrograde transport. The effect of phorbol esters was partially reversed by rottlerin and Ro-31-8220. Activation of PKC has been shown to be involved in the disorganization of actin filaments. In this study, we show that Ro-31-8220 reverses growth cone collapse by phorbol 12-myristate 13-acetate and suggest that one of the effects of activating PKC on retrograde transport is to disrupt the actin filaments.


Subject(s)
Axonal Transport/physiology , Nerve Growth Factors/metabolism , Protein Kinase C/metabolism , Receptor, Nerve Growth Factor/metabolism , Actin Cytoskeleton/drug effects , Animals , Axonal Transport/drug effects , Cell Survival/drug effects , Enzyme Activators/pharmacology , Enzyme Inhibitors/pharmacology , Eye/innervation , Eye/metabolism , Growth Cones/drug effects , Indoles/pharmacology , Male , Mice , Mice, Inbred BALB C , Nerve Growth Factors/drug effects , Neurons, Afferent/drug effects , Neurons, Afferent/metabolism , Presynaptic Terminals/drug effects , Protein Kinase C/antagonists & inhibitors , Protein Kinase C/drug effects , Receptor, trkA/metabolism , Superior Cervical Ganglion/metabolism , Sympathetic Nervous System/metabolism , Tetradecanoylphorbol Acetate/pharmacology , Trigeminal Ganglion/metabolism
12.
Mol Cell Neurosci ; 19(4): 485-500, 2002 Apr.
Article in English | MEDLINE | ID: mdl-11988017

ABSTRACT

During development the viability of immature neurons may depend upon retrograde, anterograde, or paracrine trophic support. Using (125)I-labeled peptides we show that there is substantial and rapid anterograde transport of brain-derived neurotrophic factor (BDNF) and, to a lesser extent, neurotrophin-4/5 (NT-4/5) to central visual target areas in the neonatal rat brain. Six hours after unilateral intraocular injection, all retinorecipient regions in the thalamus and midbrain are heavily labeled. Intraocular application of physiologically relevant doses of neurotrophin has a marked effect on cells in the developing superior colliculus (SC): 24 h postinjection of BDNF or NT-4/5, the number of pyknotic profiles in the contralateral superficial SC significantly decreases, while total cell numbers increase relative to ipsilateral SC. This increase is primarily associated with neurons. The data support the hypothesis that BDNF and NT-4/5 are anterograde survival factors for postsynaptic cells in the developing rat SC.


Subject(s)
Axonal Transport/physiology , Brain-Derived Neurotrophic Factor/metabolism , Brain/growth & development , Cell Differentiation/physiology , Cell Survival/physiology , Nerve Growth Factors/metabolism , Neurons/metabolism , Visual Pathways/growth & development , Animals , Animals, Newborn , Brain/drug effects , Brain/metabolism , Brain-Derived Neurotrophic Factor/pharmacology , Cell Count , Cell Differentiation/drug effects , Cell Survival/drug effects , Coloring Agents , Iodine Radioisotopes , Mice , Mice, Inbred BALB C , Nerve Growth Factors/pharmacology , Neuroglia/cytology , Neuroglia/metabolism , Neurons/cytology , Neurons/drug effects , Presynaptic Terminals/drug effects , Presynaptic Terminals/metabolism , Presynaptic Terminals/ultrastructure , Rats , Rats, Wistar , Retinal Ganglion Cells/cytology , Retinal Ganglion Cells/drug effects , Retinal Ganglion Cells/metabolism , Superior Colliculi/drug effects , Superior Colliculi/growth & development , Superior Colliculi/metabolism , Visual Pathways/drug effects , Visual Pathways/metabolism
13.
Int J Dev Neurosci ; 20(1): 39-46, 2002 Feb.
Article in English | MEDLINE | ID: mdl-12008073

ABSTRACT

Our laboratory has generated a genetically mutant mouse in which the alpha subunit of the heterotrimeric GTP binding protein, G(z) has been made dysfunctional by homologous recombination to determine its in vivo function. These animals show a characteristic failure to thrive phenotype. G(z alpha) is expressed in a variety of nervous system tissues as well as in the adrenal medulla. We therefore examined the autonomic nervous system of the G(z alpha) deficient mouse by measuring the activity of tyrosine hydroxylase and choline acetyltransferase in the superior cervical ganglia, submaxillary gland and the adrenal medulla. Preliminary results using animals of mixed BALB/c and C57BL/6 strains gave inconsistent results. Further experiments demonstrated differences in the activity of tyrosine hydroxylase and choline acetyltransferase between BALB/c and C57BL/6 mouse strains. The analysis of the pure strains showed a reduction in the size and enzyme levels of the adrenal gland and submaxillary glands of the G(z alpha) deficient mouse suggesting a role for adrenal insufficiency and/or nutritional disorders for the failure to thrive phenotype. The survival of sympathetic and sensory neurons was also examined in the G(z alpha) deficient mouse and in the presence of pertussis toxin, sympathetic but not sensory neuronal survival in G(z alpha) deficient mice was significantly attenuated. This suggests that in vivo other pertussis toxin sensitive G proteins may be recruited to compensate for the loss of G(z alpha).


Subject(s)
Autonomic Nervous System Diseases/enzymology , Autonomic Nervous System/enzymology , Autonomic Nervous System/growth & development , Cell Survival/genetics , GTP-Binding Protein alpha Subunits , GTP-Binding Proteins/deficiency , Nerve Degeneration/enzymology , Neurons/enzymology , Adrenal Medulla/enzymology , Adrenal Medulla/growth & development , Adrenal Medulla/innervation , Aging/metabolism , Animals , Autonomic Nervous System/cytology , Autonomic Nervous System Diseases/genetics , Autonomic Nervous System Diseases/physiopathology , Cells, Cultured , Choline O-Acetyltransferase/genetics , Choline O-Acetyltransferase/metabolism , Dose-Response Relationship, Drug , Female , GTP-Binding Proteins/genetics , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Nerve Degeneration/genetics , Nerve Degeneration/physiopathology , Nerve Growth Factor/pharmacology , Neurons/cytology , Neurons, Afferent/cytology , Neurons, Afferent/enzymology , Pertussis Toxin , Submandibular Gland/enzymology , Submandibular Gland/growth & development , Submandibular Gland/innervation , Tyrosine 3-Monooxygenase/genetics , Tyrosine 3-Monooxygenase/metabolism , Virulence Factors, Bordetella/pharmacology
14.
J Neurosci Res ; 68(2): 169-75, 2002 Apr 15.
Article in English | MEDLINE | ID: mdl-11948662

ABSTRACT

Phosphatidylinositol 3-kinase (PI3-kinase) and phosphatidylinositol 4-kinase (PI4-kinase) enzymes are an important family of signaling molecules that have been implicated in the regulation of intracellular vesicle trafficking. It has previously been shown that PI3-kinase and PI4-kinase enzymes regulate neuronal survival and the retrograde axonal transport of nerve growth factor in sympathetic and sensory neurons. We have extended these studies to examine the role these enzymes play in the regulation of the retrograde axonal transport of neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) in sympathetic and sensory neurons in vivo. Wortmannin (0.1 nmol/eye), a PI3-kinase and PI4-kinase antagonist, reduced the amount of (125)I-NT-3 retrograde transport in sympathetic neurons by approximately 50% and (125)I-NT-4 in sympathetic neurons by approximately 40% and sensory neurons by approximately 20%. The PI3-kinase antagonist LY294002 (100 nmol/eye) reduced the retrograde axonal transport of (125)I-NT-4 in sympathetic and sensory neurons, and (125)I-NT-3 in sympathetic neurons. Phenylarsine oxide (PAO), a PI4-kinase antagonist, significantly inhibited (125)I-NT-4 retrograde axonal transport in sympathetic and sensory neurons. These results show that wortmannin-sensitive PI3-kinases and PI4-kinases may be involved in NT-3 and NT-4 retrograde axonal transport. The retrograde axonal transport of neurotrophic factors in sympathetic and sensory neurons in vivo appears to depend upon the activation of different receptors and second messenger cascades at the nerve terminal.


Subject(s)
Axonal Transport/physiology , Biological Transport, Active/physiology , Neurons, Afferent/metabolism , Neurons/metabolism , Phosphatidylinositol 3-Kinases/physiology , Sympathetic Nervous System/metabolism , Androstadienes/pharmacology , Animals , Arsenicals/pharmacology , Axonal Transport/drug effects , Biological Transport, Active/drug effects , Chromones/pharmacology , Enzyme Inhibitors/pharmacology , Female , Iris/innervation , Male , Mice , Mice, Inbred BALB C , Morpholines/pharmacology , Nerve Growth Factors/metabolism , Neurotrophin 3/metabolism , Phosphoinositide-3 Kinase Inhibitors , Receptor, trkA/antagonists & inhibitors , Sympathetic Nervous System/cytology , Tyrphostins/pharmacology , Wortmannin
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