Protein Kinase Cδ Negatively Regulates Tyrosine Hydroxylase Activity and Dopamine Synthesis by Enhancing Protein Phosphatase-2A Activity in Dopaminergic Neurons

Zhang, Danhui; Kanthasamy, Arthi; Yang, Yongjie; Anantharam, Vellareddy; Kanthasamy, Anumantha G.

doi:10.1523/jneurosci.4107-06.2007

Cited by 95 publications

(117 citation statements)

References 72 publications

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“…Recent evidence supports the specific involvement of the calcium-independent isoform PKC-␦ in IL-6/gp130 signal transduction (Jain et al, 1999;Novotny-Diermayr et al, 2002). Indeed, we observed translocation of PKC-␦ after stimulating sensory neurons with IL-6 and IL-6-induced increases in I caps were significantly reduced in the presence of the rottlerin, which inhibits PKC-␦ in neurons (Zhang et al, 2007) but which may have additional effects (Soltoff, 2007). The structure of TRPV1 exhibits several intracellular phosphorylation sites comprising targets for protein kinases like PKA, PKC or PTK (Vellani et al, 2001;Bhave et al, 2002Bhave et al, , 2003Rathee et al, 2002;Jin et al, 2004;Jung et al, 2004;Zhang et al, 2005;Mandadi et al, 2006), and phosphorylation at these sites leaves the channel in a state of increased activity (Numazaki et al, 2002;Mohapatra and Nau, 2003;Mandadi et al, 2006).…”

Section: Discussionsupporting

confidence: 84%

A Key Role for gp130 Expressed on Peripheral Sensory Nerves in Pathological Pain

et al. 2009

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Interleukin-6 (IL-6) is a key mediator of inflammation. Inhibitors of IL-6 or of its signal transducing receptor gp130 constitute a novel class of anti-inflammatory drugs, which raise great hopes for improved treatments of painful inflammatory diseases such as rheumatoid arthritis. IL-6 and gp130 may enhance pain not only indirectly through their proinflammatory actions but also through a direct action on nociceptors (i.e., on neurons activated by painful stimuli). We found indeed that the IL-6/gp130 ligand-receptor complex induced heat hypersensitivity both in vitro and in vivo. This process was mediated by activation of PKC-␦ via Gab1/2/PI 3 K and subsequent regulation of TRPV1, a member of the transient receptor potential (TRP) family of ion channels. To assess the relevance of this direct pain promoting effect of IL-6, we generated conditional knock-out mice, which lack gp130 specifically in nociceptors, and tested them in models of inflammatory and tumor-induced pain. These mice showed significantly reduced levels of inflammatory and tumor-induced pain but no changes in immune reactions or tumor growth. Our results uncover the significance of gp130 expressed in peripheral pain sensing neurons in the pathophysiology of major clinical pain disorders and suggest their use as novel pain relieving agents in inflammatory and tumor pain.

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Section: Discussionsupporting

confidence: 84%

A Key Role for gp130 Expressed on Peripheral Sensory Nerves in Pathological Pain

et al. 2009

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“…Therefore, our findings indicate that PKC-␦ regulates ganglion cell death in OLETF rats through upregulating PP2A that dephosphorylates phospho-Akt (Ser473), competing with Akt stabilization by HSP90. A recent study reported that PKC-␦ enhances PP2A by its direct binding (27). Consistently, downregulation of PKC-␦ by rottlerin or siRNA decreased both PP2A protein levels and phosphatase activity in 35-week OLETF rat retinas.…”

Section: Discussionmentioning

confidence: 53%

Protein Kinase C-δ Mediates Neuronal Apoptosis in the Retinas of Diabetic Rats via the Akt Signaling Pathway

Kim

Park

et al. 2008

Diabetes

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OBJECTIVE-Protein kinase C (PKC)-␦, an upstream regulator of the Akt survival pathway, contributes to cellular dysfunction in the pathogenesis of diabetes. Herein, we examined the role of PKC-␦ in neuronal apoptosis through Akt in the retinas of diabetic rats.RESEARCH DESIGN AND METHODS-We used retinas from 24-and 35-week-old male Otsuka Long-Evans Tokushima fatty (OLETF) diabetic and Long-Evans Tokushima Otsuka (LETO) nondiabetic rats. To assess whether PKC-␦ affects Akt signaling and cell death in OLETF rat retinas, we examined 1) PKC-␦ activity and apoptosis; 2) protein levels of phosphatidylinositol 3-kinase (PI 3-kinase) p85, heat shock protein 90 (HSP90), and protein phosphatase 2A (PP2A); 3) Akt phosphorylation; and 4) Akt binding to HSP90 or PP2A in LETO and OLETF retinas in the presence or absence of rottlerin, a highly specific PKC-␦ inhibitor, or small interfering RNAs (siRNAs) for PKC-␦ and HSP90.RESULTS-In OLETF retinas from 35-week-old rats, ganglion cell death, PKC-␦ and PP2A activity, and Akt-PP2A binding were significantly increased and Akt phosphorylation and Akt-HSP90 binding were decreased compared with retinas from 24-week-old OLETF and LETO rats. Rottlerin and PKC-␦ siRNA abrogated these effects in OLETF retinas from 35-week-old rats. HSP90 siRNA significantly increased ganglion cell death and Akt-PP2A complexes and markedly decreased HSP90-Akt binding and Akt phosphorylation in LETO retinas from 35-week-old rats compared with those from nontreated LETO rats.CONCLUSIONS-PKC-␦ activation contributes to neuro-retinal apoptosis in diabetic rats by inhibiting Akt-mediated signaling pathways. Diabetes 57:2181-2190, 2008 P rotein kinase C (PKC)-␦, a ubiquitously expressed isoform of the novel PKC subfamily, mediates an anti-apoptotic signaling cascade through the phosphatidylinositol 3-kinase (PI 3-kinase)-mediated survival pathway (1,2) and also promotes apoptosis by interfering with Akt signaling (3-5).Akt is a downstream target of PI 3-kinase that plays an integral role in cell survival. Dysregulation of Akt is frequently observed in diseases such as cancers and diabetes (6 -8). PI 3-kinase activates Akt through the phosphorylation of two key regulatory residues, Thr308 and Ser473, on Akt. Phosphorylation of both residues is necessary for full activation of Akt and subsequent regulation of many PI 3-kinase-mediated biological responses (9,10).Protein phosphatase 2A (PP2A), a major cellular serine/ threonine phosphatase, regulates the phosphorylation state of cellular proteins in various pathological conditions (11-13). Recently, it has been reported that PP2A is involved in the regulation of cell proliferation and survival through its ability to dephosphorylate Akt (11-15). Furthermore, heat shock protein 90 (HSP90) counteracts the effect of PP2A in cells through direct binding to Akt, protecting Akt from PP2A-mediated dephosphorylation and thus functioning as a positive regulator of Akt signaling (13,15,16). Of note, numerous reports have suggested that Akt-or HSP-mediated cytoprotection is r...

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“…on March 28, 2019. by guest www.bloodjournal.org From and regulate the catalytic activity of a serine threonine phosphatase PP2Ac and modulate the dopamine production in the neuronal cells. 40 From our study, PKC-␦ regulates GPVI-mediated SHIP-1 phosphorylation and not PAR-mediated SHIP-1 phosphorylation ( Figure 3). As the phosphorylation of SHIP-1 in PKC-␦ null murine platelets is not completely ablated, we predict a role for other kinases in phosphorylating SHIP-1 on GPVI stimulation.…”

mentioning

confidence: 71%

Lyn, PKC-δ, SHIP-1 interactions regulate GPVI-mediated platelet-dense granule secretion

Chari

Kim

Murugappan

et al. 2009

Blood

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Protein kinase C-␦ (PKC-␦) is expressed in platelets and activated downstream of protease-activated receptors (PARs) and glycoprotein VI (GPVI) receptors. We have previously shown that PKC-␦ positively regulates PAR-mediated dense granule secretion, whereas it negatively regulates GPVI-mediated dense granule secretion. We further investigated the mechanism of such differential regulation of dense granule release by PKC-␦ in platelets. SH2 domain-containing inositol phosphatase-1 (SHIP-1) is phosphorylated on Y1020, a marker for its activation, upon stimulation of human platelets with PAR agonists SFLLRN and AYPGKF or GPVI agonist convulxin. GPVI-mediated SHIP-1 phosphorylation occurred rapidly at 15 seconds, whereas PAR-mediated phosphorylation was delayed, occurring at 1 minute. Lyn and SHIP-1, but not SHIP-2 or Shc, preferentially associated with PKC-␦ on stimulation of platelets with a GPVI agonist, but not with a PAR agonist. In PKC-␦-null murine platelets, convulxin-induced SHIP-1 phosphorylation was inhibited. IntroductionPlatelet-collagen interactions are thought to have the greatest significance at medium or high shear rates found in arteries and diseased vessels. 1 Glycoprotein VI (GPVI) is the major signaling receptor for collagen on the platelet surface. 1 The critical role played by platelets in hemostasis, thrombosis and vascular remodeling, and healing is related to their function as exocytotic cells that secrete important effector molecules at the site of vascular injury. Platelets normally contain at least 3 types of large intracellular granules, such as ␣, dense, and lysosomal granules. There are 3 to 8 dense granules per platelet, and the contents from these dense granules are important for recruiting more platelets to the site of injury. 2,3 Protein kinase C (PKC) has been implicated in platelet secretion. 4 Protein kinase Cs are members of the extended AGC (protein kinases A, G, and C) family of differentially expressed serine/ threonine kinases implicated in a diverse array of cellular functions. After activation, these kinases migrate to different subcellular locations, including the plasma membrane and cytoskeletal elements where they regulate different physiologic functions. 5 PKC isoforms are subdivided into 3 groups based on their lipid and cofactor requirements: the diacylglycerol and calcium-sensitive conventional isoforms (␣, ␤I, ␤II and ␥), the diacylglycerolsensitive and calcium-insensitive novel isoforms (␦, , , and ⑀), and the phosphatidylinositide trisphosphate-sensitive atypical isoforms (, , , and ). 6 PKC-␦ plays a key role in growth regulation and tissue remodeling in other cells 7 and differentially regulates dense granule secretion in platelets. It positively regulates proteaseactivated receptor (PAR)-mediated dense granule release and negatively regulates GPVI-mediated dense granule release. [8][9][10] Intrinsic function of PKCs is regulated by 3 mechanisms: (1) binding of the cofactor that allosterically activates the enzyme, (2) phosphorylation on the activation loop r...

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Protein Kinase Cδ Negatively Regulates Tyrosine Hydroxylase Activity and Dopamine Synthesis by Enhancing Protein Phosphatase-2A Activity in Dopaminergic Neurons

Cited by 95 publications

References 72 publications

A Key Role for gp130 Expressed on Peripheral Sensory Nerves in Pathological Pain

A Key Role for gp130 Expressed on Peripheral Sensory Nerves in Pathological Pain

Protein Kinase C-δ Mediates Neuronal Apoptosis in the Retinas of Diabetic Rats via the Akt Signaling Pathway

Lyn, PKC-δ, SHIP-1 interactions regulate GPVI-mediated platelet-dense granule secretion

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