Pharmacological PKA Inhibition: All May Not Be What It Seems

Murray, Andrew

doi:10.1126/scisignal.122re4

Cited by 287 publications

(262 citation statements)

References 64 publications

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“…reported to inhibit other protein kinases such as phosphoinositide-dependent kinase-1 (PDK-1) and mitogen and extracellular signal-regulated kinases kinase (MEK) (33). Our results cannot exclude the possibility that KT5720 hides the action of other factors rather than PKA.…”

Section: Discussioncontrasting

confidence: 49%

Relaxant Effect of Prostaglandin D2–Receptor DP Agonist on Liver Myofibroblast Contraction

et al. 2011

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Abstract. Increased intrahepatic resistance causes portal hypertension in cirrhosis. Liver myofibroblasts (MFs) are now regarded as the principle cells involved in sinusoidal blood flow regulation. Many other prostaglandin-receptor agonists have been reported to regulate liver MF contraction, but the role of the prostaglandin D 2 -receptor DP is unknown. In this study, we investigated the effect of a synthetic agonist of prostanoid DP receptor, BW245C, on contractile properties of primary rat liver MFs. Collagen gel contraction assay revealed that BW245C alone (1 and 10 μM) did not induce contraction but induced cell relaxation. Pretreatment with BW245C (10 μM, 30 min) attenuated bradykinin (100 nM)-induced liver MF contraction. Elevation of [Ca 2+ ] i induced by bradykinin (100 nM) was partially suppressed by BW245C pretreatment (10 μM, 3 min). BW245C (1 and 10 μM) significantly increased intracellular cAMP level in a dose-dependent manner. Pretreatment with forskolin (30 -300 nM, 30 min) and dibutyryl-cAMP (3 -30 μM, 30 min) significantly reduced bradykinin-induced contraction. Furthermore, a protein kinase A (PKA) inhibitor KT5720 (10 nM to 1 μM, 30 min) blocked the relaxant effect of BW245C. These results suggest that prostanoid DP receptor agonism inhibits bradykinin-induced [Ca 2+ ] i elevation and contraction through cAMP-PKA signal activation in rat liver MFs.

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Section: Discussioncontrasting

confidence: 49%

Relaxant Effect of Prostaglandin D2–Receptor DP Agonist on Liver Myofibroblast Contraction

et al. 2011

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“…To further investigate the relationship between 14-3-3 proteins and cAMP-dependent signaling we asked whether R18-dependent switching in an NGF gradient would be affected by applying the cAMP antagonist Rp-cAMPs or the protein kinase A antagonists KT-5720 or PKI (Kase et al, 1987;Dalton and Dewey, 2006). Both the small molecule inhibitor KT-5720 and the myristoylated peptide PKI act by targeting the catalytic subunit of the PKA holoenzyme I and together these inhibitors selectively address the function of PKA (Murray, 2008). As expected, inhibition of cAMP or PKA did not impact NGF-dependent repulsion in WLRL-transduced E13 chick DRGs; a stage with low levels of cAMP ( Fig.…”

Section: -3-3 Proteins Switch Ngf-dependent Growth Cone Turning Resmentioning

confidence: 99%

14-3-3 Proteins Regulate Protein Kinase A Activity to Modulate Growth Cone Turning Responses

Kent¹,

Shimada²,

Ferraro³

et al. 2010

J. Neurosci.

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Growth cones regulate the speed and direction of neuronal outgrowth during development and regeneration. How the growth cone spatially and temporally regulates signals from guidance cues is poorly understood. Through a proteomic analysis of purified growth cones we identified isoforms of the 14-3-3 family of adaptor proteins as major constituents of the growth cone. Disruption of 14-3-3 via the R18 antagonist or knockdown of individual 14-3-3 isoforms switches nerve growth factor-and myelin-associated glycoproteindependent repulsion to attraction in embryonic day 13 chick and postnatal day 5 rat DRG neurons. These effects are reminiscent of switching responses observed in response to elevated cAMP. Intriguingly, R18-dependent switching is blocked by inhibitors of protein kinase A (PKA), suggesting that 14-3-3 proteins regulate PKA. Consistently, 14-3-3 proteins interact with PKA and R18 activates PKA by dissociating its regulatory and catalytic subunits. Thus, 14-3-3 heterodimers regulate the PKA holoenzyme and this activity plays a critical role in modulating neuronal responses to repellent cues.

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“…S4B). Ruling out possible nonspecific effects of H89 (27), adenovirus-mediated knockdown of hepatic PKA expression with Ad-shPKA abolished glucagon-stimulated but not thapsigargininduced phosphorylation of IRE1α (Fig. 3C).…”

Section: Ire1αmentioning

confidence: 99%

PKA phosphorylation couples hepatic inositol-requiring enzyme 1α to glucagon signaling in glucose metabolism

Mao

Shao

Qiu

et al. 2011

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

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The endoplasmic reticulum (ER)-resident protein kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1) is activated through transautophosphorylation in response to protein folding overload in the ER lumen and maintains ER homeostasis by triggering a key branch of the unfolded protein response. Here we show that mammalian IRE1α in liver cells is also phosphorylated by a kinase other than itself in response to metabolic stimuli. Glucagon-stimulated protein kinase PKA, which in turn phosphorylated IRE1α at Ser 724 , a highly conserved site within the kinase activation domain. Blocking Ser 724 phosphorylation impaired the ability of IRE1α to augment the up-regulation by glucagon signaling of the expression of gluconeogenic genes. Moreover, hepatic IRE1α was highly phosphorylated at Ser 724 by PKA in mice with obesity, and silencing hepatic IRE1α markedly reduced hyperglycemia and glucose intolerance. Hence, these results suggest that IRE1α integrates signals from both the ER lumen and the cytoplasm in the liver and is coupled to the glucagon signaling in the regulation of glucose metabolism.endoplasmic reticulum stress | G protein-coupled receptor | metabolic disease

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Pharmacological PKA Inhibition: All May Not Be What It Seems

Cited by 287 publications

References 64 publications

Relaxant Effect of Prostaglandin D2–Receptor DP Agonist on Liver Myofibroblast Contraction

Relaxant Effect of Prostaglandin D2–Receptor DP Agonist on Liver Myofibroblast Contraction

14-3-3 Proteins Regulate Protein Kinase A Activity to Modulate Growth Cone Turning Responses

PKA phosphorylation couples hepatic inositol-requiring enzyme 1α to glucagon signaling in glucose metabolism

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