PKA catalytic subunit compartmentation regulates contractile and hypertrophic responses to β-adrenergic signaling

Yang, Jason H.; Polanowska-Grabowska, Renata; Smith, Jeffrey S.; Shields, C. Wyatt; Saucerman, Jeffrey J.

doi:10.1016/j.yjmcc.2013.11.001

Cited by 47 publications

(40 citation statements)

References 66 publications

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“…Conversely, PDE4D3 overexpression inhibits nuclear PKA activity [63]. Importantly, nuclear PKA plays a central role in the hypertrophic response as nuclear PKA catalytic subunit overexpression in cardiomyocytes induces hypertrophy [55]. This result is consistent with our observation that UCR1C reduces nuclear PKA activity, which may explain the ability of UCR1C to inhibit ISO-induced hypertrophy.…”

Section: Discussionsupporting

confidence: 86%

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UCR1C is a novel activator of phosphodiesterase 4 (PDE4) long isoforms and attenuates cardiomyocyte hypertrophy

Wang

Burmeister

Johnson

et al. 2015

Cellular Signalling

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Hypertrophy increases the risk of heart failure and arrhythmia. Prevention or reversal of the maladaptive hypertrophic phenotype has thus been proposed to treat heart failure. Chronic β-adrenergic receptor (β-AR) stimulation induces cardiomyocyte hypertrophy by elevating 3′, 5′-cyclic adenosine monophosphate (cAMP) levels and activating downstream effectors such protein kinase A (PKA). Conversely, hydrolysis of cAMP by phosphodiesterases (PDEs) spatiotemporally restricts cAMP signaling. Here, we demonstrate that PDE4, but not PDE3, is critical in regulating cardiomyocyte hypertrophy, and may represent a potential target for preventing maladaptive hypertrophy. We identify a sequence within the upstream conserved region 1 of PDE4D, termed UCR1C, as a novel activator of PDE4 long isoforms. UCR1C activates PDE4 in complex with A-Kinase anchoring protein (AKAP)-Lbc resulting in decreased PKA signaling facilitated by AKAP-Lbc. Expression of UCR1C in cardiomyocytes inhibits hypertrophy in response to chronic β-AR stimulation. This effect is partially due to inhibition of nuclear PKA activity, which decreases phosphorylation of the transcription factor cAMP response element-binding protein (CREB). In conclusion, PDE4 activation by UCR1C attenuates cardiomyocyte hypertrophy by specifically inhibiting nuclear PKA activity.

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Section: Discussionsupporting

confidence: 86%

“…These results suggest that UCR1C specifically inhibits nuclear PKA activity. Combined with the recent report that nuclear overexpression of PKA-C induces cardiomyocyte hypertrophy [55], these findings suggest that nuclear PKA activity is critical for cardiomyocyte hypertrophy.…”

Section: Resultssupporting

confidence: 55%

UCR1C is a novel activator of phosphodiesterase 4 (PDE4) long isoforms and attenuates cardiomyocyte hypertrophy

Wang

Burmeister

Johnson

et al. 2015

Cellular Signalling

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“…We also compared the ATP-evoked intracellular calcium mobilization of DRG neurons from control and TNBS-treated rats, in the presence of NE at 20 M. Surprisingly, the ATP-evoked intracellular calcium mobilization in the presence of NE at 20 M was more significantly enhanced in CP rats than in age-matched control rats ( PKA is involved in NE-induced potentiation of ATP responses. Because PKA is known to participate in the actions of NE (46), its role in the potentiation of ATP responses was then studied. We first determined the effect of H-89, a membrane-permeable PKA inhibitor, on the enhancement of ATP responses by NE.…”

Section: Resultsmentioning

confidence: 99%

Adrenergic signaling mediates mechanical hyperalgesia through activation of P2X3 receptors in primary sensory neurons of rats with chronic pancreatitis

Wang

Zhu

Jin

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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. Adrenergic signaling mediates mechanical hyperalgesia through activation of P2X3 receptors in primary sensory neurons of rats with chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol 308: G710 -G719, 2015. First published January 29, 2015; doi:10.1152/ajpgi.00395.2014.-The mechanism of pain in chronic pancreatitis (CP) is poorly understood. The aim of this study was designed to investigate roles of norepinephrine (NE) and P2X receptor (P2XR) signaling pathway in the pathogenesis of hyperalgesia in a rat model of CP. CP was induced in male adult rats by intraductal injection of trinitrobenzene sulfonic acid (TNBS). Mechanical hyperalgesia was assessed by referred somatic behaviors to mechanical stimulation of rat abdomen. P2XR-mediated responses of pancreatic dorsal root ganglion (DRG) neurons were measured utilizing calcium imaging and whole cell patch-clamp-recording techniques. Western blot analysis and immunofluorescence were performed to examine protein expression. TNBS injection produced a significant upregulation of P2X3R expression and an increase in ATP-evoked responses of pancreatic DRG neurons. The sensitization of P2X3Rs was reversed by administration of ␤-adrenergic receptor antagonist propranolol. Incubation of DRG neurons with NE significantly enhanced ATPinduced intracellular calcium signals, which were abolished by propranolol, and partially blocked by protein kinase A inhibitor H-89. Interestingly, TNBS injection led to a significant elevation of NE concentration in DRGs and the pancreas, an upregulation of ␤ 2-adrenergic receptor expression in DRGs, and amplification of the NE-induced potentiation of ATP responses. Importantly, pancreatic hyperalgesia was markedly attenuated by administration of purinergic receptor antagonist suramin or A317491 or ␤ 2-adrenergic receptor antagonist butoxamine. Sensitization of P2X3Rs, which was likely mediated by adrenergic signaling in primary sensory neurons, contributes to pancreatic pain, thus identifying a potential target for treating pancreatic pain caused by inflammation. chronic pancreatitis; dorsal root ganglion; purinergic receptors; norepinephrine; protein kinase A CHRONIC PANCREATITIS (CP) is a progressive inflammatory disorder characterized by repeated attacks of abdominal pain, fibrosis, and destruction of the glandular pancreas (15,29,39). Pain is a cardinal feature of CP, featured as burning, intermittent, and shooting pain (13). It is, not only the most frequent and dominant symptom of patients with CP, but also the most difficult to treat (1,3,22,35). Our lack of knowledge about what causes pain in pancreatitis has been a serious obstacle to treatment on these patients, with pain frequently relapsing or persisting (1, 31). Basic research of pancreatic nerves and experimental human pain studies have provided evidence that pain processing is abnormal in these patients and in many conditions resembles that seen in neuropathic pain disorders (34). Despite much speculation, little is known about the detailed pathophysiology of pain in ...

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“…This is proposed to explain how the reduced fractional PKA-C content in the diabetic heart significantly effects PKA substrate phosphorylation and cardiac function. Other contributing factors include the reduced PKI content, which would help maintain nuclear phosphorylation despite reduced PKA content (35).…”

Section: Discussionmentioning

confidence: 99%

cAMP-dependent Protein Kinase (PKA) Signaling Is Impaired in the Diabetic Heart

Humphries

2015

Journal of Biological Chemistry

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Diabetes mellitus causes cardiac dysfunction and heart failure that is associated with metabolic abnormalities and autonomic impairment. Autonomic control of ventricular function occurs through regulation of cAMP-dependent protein kinase (PKA). The diabetic heart has suppressed ␤-adrenergic responsiveness, partly attributable to receptor changes, yet little is known about how PKA signaling is directly affected. Control and streptozotocin-induced diabetic mice were therefore administered 8-bromo-cAMP (8Br-cAMP) acutely to activate PKA in a receptorindependent manner, and cardiac hemodynamic function and PKA signaling were evaluated. In response to 8Br-cAMP treatment, diabetic mice had impaired inotropic and lusitropic responses, thus demonstrating postreceptor defects. This impaired signaling was mediated by reduced PKA activity and PKA catalytic subunit content in the cytoplasm and myofilaments. Compartment-specific loss of PKA was reflected by reduced phosphorylation of discrete substrates. In response to 8Br-cAMP treatment, the glycolytic activator PFK-2 was robustly phosphorylated in control animals but not diabetics. Control adult cardiomyocytes cultured in lipid-supplemented media developed similar changes in PKA signaling, suggesting that lipotoxicity is a contributor to diabetes-induced ␤-adrenergic signaling dysfunction. This work demonstrates that PKA signaling is impaired in diabetes and suggests that treating hyperlipidemia is vital for proper cardiac signaling and function.Diabetes mellitus carries at least twice the risk of cardiovascular complications such as coronary artery disease, hypertension, and heart failure (1, 2). Diabetes can directly cause heart failure, in the case of diabetic cardiomyopathy, as well as exacerbate other comorbidities (3, 4). The reasons for this are multifaceted and involve both metabolic and mechanical cardiac stresses. Metabolic abnormalities include metabolic inflexibility caused by improper glucose uptake and oxidation and by lipotoxicity induced by lipid overload (5). Diabetes, in common with other forms of heart failure, has impairment of autonomic control and overstimulation of the sympathetic nervous system (6, 7). The etiology of chronic cardiac stimulation in diabetes is characterized by sympathetic enhancement and parasympathetic withdrawal (3, 8). Excess sympathetic stimulation over time causes extensive dysfunction to the ␤-adrenergic pathway, a process that is intimately tied with heart failure (9, 10).Normally, ligand binding to ␤ 1 -receptors activates G s proteins, which stimulate adenylate cyclase to produce cAMP. The primary target of cAMP is cAMP-dependent protein kinase (PKA), 2 a heterotetrameric protein comprised of two catalytic (PKA-C) and two regulatory subunits (either PKA-RI or PKA-RII isoforms). cAMP binds PKA-R subunits and induces the release of PKA-C, which then phosphorylates specific serines and threonines on protein targets in the cytoplasm, myofilaments, sarcoplasmic reticulum, sarcolemma, and nucleus to increase cardiac output, metab...

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PKA catalytic subunit compartmentation regulates contractile and hypertrophic responses to β-adrenergic signaling

Cited by 47 publications

References 66 publications

UCR1C is a novel activator of phosphodiesterase 4 (PDE4) long isoforms and attenuates cardiomyocyte hypertrophy

UCR1C is a novel activator of phosphodiesterase 4 (PDE4) long isoforms and attenuates cardiomyocyte hypertrophy

Adrenergic signaling mediates mechanical hyperalgesia through activation of P2X3 receptors in primary sensory neurons of rats with chronic pancreatitis

cAMP-dependent Protein Kinase (PKA) Signaling Is Impaired in the Diabetic Heart

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