cGMP-dependent Protein Kinase Inhibits Serum-response Element-dependent Transcription by Inhibiting Rho Activation and Functions

Gudi, Tanima; Chen, Jeffrey C.; Casteel, Darren E.; Seasholtz, Tammy M.; Boss, Gerry R.; Pilz, Renate B.

doi:10.1074/jbc.m204491200

Cited by 82 publications

(103 citation statements)

References 73 publications

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“…5 C and D). PKG1 has an established role in directly phosphorylating CREB, and this activity may depend on nuclear shuttling of PKG1 (18). In line with this result, the effect of cGMP was completely abolished by PKG1 inhibition (106 ± 15% of basal phosphorylation level) (Fig.…”

Section: ) (E)supporting

confidence: 75%

Nitric oxide regulates synaptic transmission between spiny projection neurons

Sagi

Heiman

Peterson

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance The function of the basal ganglia relies on striatal spiny projecting neurons (SPNs). Axon collaterals of these GABAergic neurons form connections with other SPNs as a means of a feedback inhibition circuit. The mechanisms that regulate neurotransmission at these local synapses remain poorly understood. In this paper, neurotransmission at SPN collaterals is found to be regulated by the gaseous neurotransmitter nitric oxide, which activates a signal-transduction cascade that transcriptionally regulates vesicular GABA transporter specifically at axon collaterals. These findings illustrate a previously unidentified role for nitric oxide in striatal learning and action selection.

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Section: ) (E)supporting

confidence: 75%

Nitric oxide regulates synaptic transmission between spiny projection neurons

Sagi

Heiman

Peterson

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…This inhibition is associated with a decrease in the amount of active GTP-bound RhoA in cells stimulated with serum or constitutively active G␣ 12 or G␣ 13 , but not in p115 RhoGEF -or RhoA L63 -expressing cells, suggesting that PKG can act both upstream and downstream of RhoA. The effect on steps downstream of RhoA has been confirmed by showing that SRE-dependent transcription mediated by a constitutively active RhoA effector (ROK, PKN, or PRK-2) is inhibited by PKG activation (14). Therefore, the effects of the NO/cGMP/PKG signaling pathway on membrane-bound active GTP-bound RhoA in stimulated cells are beginning to be well documented.…”

supporting

confidence: 54%

“…Several additional reports have now confirmed the inhibitory effect of the NO/cGMP/PKG signaling pathway on the RhoA-dependent component of agonist-induced contraction (10 -13). Recently, it has also been shown that PKG inhibits RhoA-mediated serum response element (SRE)-dependent transcription (14). PKG inhibits SRE-dependent transcription induced by serum, constitutively active G␣ 12 or G␣ 13 , constitutively active Rho exchange factor p115 RhoGEF , or constitutively active RhoA L63 .…”

mentioning

confidence: 99%

RhoA Expression Is Controlled by Nitric Oxide through cGMP-dependent Protein Kinase Activation

Sauzeau¹,

Rolli–Derkinderen²,

Marionneau

et al. 2003

Journal of Biological Chemistry

167

128

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Small G proteins of the Rho family function as tightly regulated molecular switches that govern a wide range of cell functions (1). A large body of evidence has now been obtained regarding the important functions of Rho proteins in the vasculature, and RhoA has been shown to play a major role in vascular processes such as smooth muscle cell contraction, proliferation, and differentiation; endothelial permeability; platelet activation; and leukocyte migration (2-4). The activity of Rho is under the direct control of a large set of other regulatory proteins (1). In the inactive GDP-bound form, RhoA is locked in the cytosol by guanine dissociation inhibitors. The guanine nucleotide exchange factors catalyze the exchange of GDP for GTP to activate RhoA (5). Activation is then turned off by GTPase-activating proteins that hydrolyze GTP to GDP. Therefore, both the relative expression of these proteins (in particular, that of RhoA) and the fraction of active GTP-bound RhoA are key determinants of RhoA protein activity.Data are now accumulating regarding the regulation of the amount of active GTP-bound RhoA. In vascular smooth muscle cells, several agonists of G protein-coupled receptors, including thrombin, thromboxane A 2 , endothelin, carbachol, angiotensin, ␣-adrenergic agonists, sphingolipids, and extracellular nucleotides, stimulate RhoA activity through the activation of guanine nucleotide exchange factors and increases in the fraction of GTP-bound RhoA. This RhoA activation is accompanied by the membrane translocation of GTP-bound RhoA (5-8). On the other hand, the NO, cGMP, and cGMP-dependent kinase (PKG) 1 signaling pathway exerts inhibitory action on RhoA functions in cells stimulated by these G protein-coupled receptor agonists. We have previously demonstrated that PKG phosphorylates RhoA at Ser 188 in vitro and that the effects of PKG activation on actin cytoskeleton are lost in cells expressing the non-phosphorylatable RhoA A188 mutant, suggesting that inhibitory effects of PKG on RhoA-mediated contraction and actin organization are due to phosphorylation of RhoA at Ser 188 (9). This effect involves inhibition of membrane translocation of GTP-bound RhoA. Several additional reports have now confirmed the inhibitory effect of the NO/cGMP/PKG signaling pathway on the RhoA-dependent component of agonist-induced contraction (10 -13). Recently, it has also been shown that PKG inhibits RhoA-mediated serum response element (SRE)-dependent transcription (14). PKG inhibits SRE-dependent transcription induced by serum, constitutively active G␣ 12 or G␣ 13 , constitutively active Rho exchange factor p115 RhoGEF , or constitutively active RhoA L63 . This inhibition is associated with a decrease in the amount of active GTP-bound RhoA in cells stimulated with serum or constitutively active G␣ 12 or G␣ 13 , but not in p115 RhoGEF -or RhoA L63 -expressing cells, suggesting that PKG can act both upstream and downstream of RhoA. The effect on steps downstream of RhoA has been confirmed by showing that SRE-dependent transcrip...

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“…Despite the involvement of PKG in the regulation of smooth muscle gene expression, regulation of transcription factors by PKG in smooth muscle is poorly understood. For example, PKG increases transcriptional activity of cyclic AMP response element-binding protein, ATF-1 (activation factor 1), TFII-I, and AP-1 (activator protein-1) in different cultured cells (48 -52) and decreases SRF (serum response factor)-dependent transcription in cultured vascular smooth cells and cardiomyocytes (53). Here, we provide the first evidence that PKG, in concert with an elevation of intracellular Ca 2ϩ , promotes the activation of a smooth muscle transcription factor, NFAT.…”

Section: Pressure Induction Of Nfatc3 Nuclear Accumulation Requires Bmentioning

confidence: 99%

Intraluminal Pressure Is a Stimulus for NFATc3 Nuclear Accumulation

Bosc¹,

Wilkerson²,

Bradley

et al. 2004

Journal of Biological Chemistry

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The transcription factor NFAT (nuclear factor of activated T-cells) is implicated in cardiac hypertrophy and vasculogenesis. NFAT activation, reflecting dephosphorylation by the calcium-dependent phosphatase, calcineurin, and subsequent nuclear localization, is generally thought to require a sustained increase in intracellular calcium. However, in smooth muscle we have found that elevation of calcium by membrane depolarization fails to induce an increase in nuclear localization of the NFATc3 isoform. Here, we demonstrate that physiological intravascular pressure (100 mm Hg) induces an increase in NFATc3 nuclear localization in mouse cerebral arteries. Pressure-induced NFATc3 nuclear accumulation is abrogated by endothelial denudation and by nitric-oxide synthase, cGMP-dependent kinase (PKG), and voltage-dependent calcium channels inhibition. We further show that exogenous nitric oxide, in combination with an elevation in calcium, is an effective stimulus for NFATc3 nuclear accumulation. c-Jun terminal kinase 2 (JNK) activity, which has been shown to regulate NFATc3 nuclear export, is also reduced by pressure, an effect that is prevented by pretreatment with a PKG inhibitor. Consistent with this, pressure-induced NFATc3 nuclear accumulation is independent of PKG in arteries from JNK2 ؊/؊ mice. Collectively, our results indicate that both activation of the NO/PKG pathway and elevation of smooth muscle calcium are required for NFATc3 nuclear accumulation and that PKG inhibits JNK2 to decrease NFAT nuclear export. Our findings suggest that at physiological intravascular pressures NFATc3 is localized to the nucleus in smooth muscle cells of intact arteries and indicate a novel and unexpected role for nitric oxide/PKG in NFAT activation.

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cGMP-dependent Protein Kinase Inhibits Serum-response Element-dependent Transcription by Inhibiting Rho Activation and Functions

Cited by 82 publications

References 73 publications

Nitric oxide regulates synaptic transmission between spiny projection neurons

Nitric oxide regulates synaptic transmission between spiny projection neurons

RhoA Expression Is Controlled by Nitric Oxide through cGMP-dependent Protein Kinase Activation

Intraluminal Pressure Is a Stimulus for NFATc3 Nuclear Accumulation

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