Protein Kinase C-Dependent Coupling of α&lt;sub&gt;2A/D&lt;/sub&gt;-Adrenergic Receptors to Phospholipase D

Jinsi-Parimoo, Arti; Deth, Richard C.

doi:10.1159/000028342

Cited by 2 publications

(2 citation statements)

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“…However, calphostin C significantly reduced retrograde axonal transport of neurotrophins (data not shown), which makes this inhibitor unsuitable for testing intracellular sorting after retrograde axonal transport. Since we cannot exclude an unlikely, but theoretically possible indirect effect of the tested kinase inhibitors on trkB or trkC phosphorylation and a downstream effect on p75NTR (even in the absence of trkA which is not expressed in the ION), we tested another kinase inhibitor, genistein, which is a relatively specific inhibitor for tyrosine kinases, but has minimal effects on PKCs (Jinsi-Parimoo and Deth, 2000). As shown in the Supplemental Table 2, genistein did not alter the delayed accumulation of NGF in MVBs and lysosomes.…”

Section: Resultsmentioning

confidence: 99%

Fates of Neurotrophins after Retrograde Axonal Transport: Phosphorylation of p75NTR Is a Sorting Signal for Delayed Degradation

Butowt

Bartheld²

2009

J. Neurosci.

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Neurotrophins can mediate survival or death of neurons. Opposing functions of neurotrophins are based on binding of these ligands to two distinct types of receptors: trk receptors and p75NTR. Previous work showed that target-derived NGF induces cell death, whereas BDNF and NT-3 enhance survival of neurons in the isthmo-optic nucleus of avian embryos. To determine the fate of retrogradely transported neurotrophins and test whether their sorting differs between neurotrophins mediating survival-or death-signaling pathways, we traced receptor-binding, sorting, and degradation kinetics of target-applied radiolabeled neurotrophins that bind in this system to trk receptors (BDNF, NT-3) or only to p75NTR (NGF). At the ultrastructural level, the p75NTR-bound NGF accumulates with a significant delay in multivesicular bodies and organelles of the degradation pathway on arrival in the cell body when compared with trk-bound BDNF or NT-3. This delayed lysosomal accumulation was restricted to target-derived NGF, but was not seen when NGF was supplied to the soma in vitro. The kinase inhibitors K252a and Gö6976 alter the kinetics of organelle accumulation: phosphorylation of p75NTR is a sorting signal for delayed sequestering of p75NTR-bound NGF in multivesicular bodies and delayed degradation in lysosomes when compared with trk-bound neurotrophins. Mutagenesis and mass spectrometry studies indicate that p75NTR is phosphorylated by conventional protein kinase C on serine 266. We conclude that, in addition to the known phosphorylation of trks, the phosphorylation of p75NTR can also significantly affect neuronal survival in vivo by changing the intracellular sorting and degradation kinetics of its ligands and thus signaling duration.

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Section: Resultsmentioning

confidence: 99%

Fates of Neurotrophins after Retrograde Axonal Transport: Phosphorylation of p75NTR Is a Sorting Signal for Delayed Degradation

Butowt

Bartheld²

2009

J. Neurosci.

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“…Our studies showed that increased resistance to mycobacterial growth requires signaling through Gi-protein ␣ subunits, as a specific antagonist of the Go/Gi family blocked the increased resistance to mycobacterial growth induced by clonidine, while an antagonist of Gs-protein ␣ subunits had no effect. ␣ 2 -Adrenergic stimulation inhibits adenylyl cyclase (15,44) and activates phospholipase C (15,29), phospholipase D (PLD) (36,47), and mitogen-activated protein (MAP) kinases (1,23,57). Which of these pathways is responsible for the increased production of peroxynitrite needs to be determined.…”

Section: Vol 71 2003 Catecholamines Increase Resistance To Mycobactmentioning

confidence: 99%

Resistance of Macrophages toMycobacterium aviumIs Induced by α₂-Adrenergic Stimulation

Weatherby¹,

Zwilling

Lafuse

2003

Infect Immun

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The ability of macrophages to control the growth of microorganisms is increased by macrophage activation. Previously, it was shown that epinephrine activated mouse macrophages to resist the growth of Mycobacterium avium via ␣ 2 -adrenergic stimulation. In the present study, we show that the ␣ 2 -adrenergic agonist (␣ 2 -agonist) clonidine induced resistance to M. avium growth in the RAW264.7 mouse macrophage cell line. The ability of catecholamines to induce resistance to mycobacteria was specific to ␣ 2 -adrenergic stimulation, as ␣ 1 -, ␤ 1 -, and ␤ 2 -agonists had no effect. Receptor signaling through Gi proteins was required. A G-protein antagonist specific for the ␣ subunits of the Go/Gi family blocked the increased resistance induced by clonidine, while a Gs-protein antagonist was without effect. Both nitric oxide (NO) production and superoxide (O 2 ؊ ) production were required for the increased resistance to M. avium growth induced by clonidine. Although NO production was required, clonidine did not increase the level of NO in M. avium-infected cells. Since NO and O 2 ؊ interact to produce peroxynitrite (ONOO ؊ ), we examined whether ONOO ؊ mediates the increased resistance to M. avium induced by clonidine. 5,10,15,20-Tetrakis(4-sulfonatophenyl)prophyrinato iron (III) chloride (FeTPPS), a specific scavenger of ONOO ؊ , inhibited the effect of clonidine on M. avium growth. Clonidine also increased the production of ONOO ؊ in M. avium-infected RAW264.7 cells, as measured by the oxidation of 123-dihydrorhodamine and the production of nitrated tyrosine residues. We therefore conclude that ␣ 2 -adrenergic stimulation activates macrophages to resist the growth of M. avium by enhancing the production of ONOO ؊ .Macrophages are among the first cells of the host to confront microbes and are important effector cells in innate resistance to intracellular microbial pathogens. The outcome of this initial encounter with an intracellular pathogen is that either the macrophage resists the growth of the microorganism or the microorganism adapts and replicates within the macrophage. The ability of the macrophage to resist the growth of the microorganism is dependent on the activation state of the macrophage. Cytokines, such as gamma interferon (IFN-␥), granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor alpha (TNF-␣), activate macrophages to resist the growth of intracellular pathogens by enhancing the production of the major antimicrobial effector molecules, including reactive oxygen species and nitric oxide (38,46,53).The sympathetic nervous system acts to maintain homeostasis during periods of stress by releasing norepinephrine at sympathetic nerve endings and epinephrine from the adrenal medulla (3,20,65). These catecholamine hormones modulate the activities of cells, including cells of the immune system (35). Macrophage function can be either activated (50,59,60) or suppressed (9,31,58,63,67) by catecholamines. A study by Boomershine et al. (9) showed that the addition of epinephrine to IFN-␥-...

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Protein Kinase C-Dependent Coupling of α<sub>2A/D</sub>-Adrenergic Receptors to Phospholipase D

Cited by 2 publications

References 20 publications

Fates of Neurotrophins after Retrograde Axonal Transport: Phosphorylation of p75NTR Is a Sorting Signal for Delayed Degradation

Fates of Neurotrophins after Retrograde Axonal Transport: Phosphorylation of p75NTR Is a Sorting Signal for Delayed Degradation

Resistance of Macrophages toMycobacterium aviumIs Induced by α₂-Adrenergic Stimulation

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Protein Kinase C-Dependent Coupling of α<sub>2A/D</sub>-Adrenergic Receptors to Phospholipase D

Cited by 2 publications

References 20 publications

Fates of Neurotrophins after Retrograde Axonal Transport: Phosphorylation of p75NTR Is a Sorting Signal for Delayed Degradation

Fates of Neurotrophins after Retrograde Axonal Transport: Phosphorylation of p75NTR Is a Sorting Signal for Delayed Degradation

Resistance of Macrophages toMycobacterium aviumIs Induced by α2-Adrenergic Stimulation

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Resistance of Macrophages toMycobacterium aviumIs Induced by α₂-Adrenergic Stimulation