scholarly journals Identification and Functional Characterization of Protein Kinase A Phosphorylation Sites in the Major Lipolytic Protein, Adipose Triglyceride Lipase

Endocrinology ◽  
2012 ◽  
Vol 153 (9) ◽  
pp. 4278-4289 ◽  
Author(s):  
Joanne Pagnon ◽  
Maria Matzaris ◽  
Romana Stark ◽  
Ruth C. R. Meex ◽  
S. Lance Macaulay ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Functional Characterization ◽  
Moderate Intensity ◽  
Adipose Triglyceride Lipase ◽  
Adrenergic Stimulation ◽  
Moderate Intensity Exercise ◽  
Triglyceride Lipase ◽  
Triacylglycerol Hydrolysis ◽  
Kinase A

Catecholamine-stimulated lipolysis occurs by activating adenylate cyclase and raising cAMP levels, thereby increasing protein kinase A (PKA) activity. This results in phosphorylation and modulated activity of several key lipolytic proteins. Adipose triglyceride lipase (ATGL) is the primary lipase for the initial step in triacylglycerol hydrolysis, and ATGL activity is increased during stimulated lipolysis. Here, we demonstrate that murine ATGL is phosphorylated by PKA at several serine residues in vitro and identify Ser406 as a functionally important site. ATGL null adipocytes expressing ATGL S406A (nonphosphorylatable) had reduced stimulated lipolysis. Studies in mice demonstrated increased ATGL Ser406 phosphorylation during fasting and moderate intensity exercise, conditions associated with elevated lipolytic rates. ATGL Ser404 (corresponding to murine Ser406) phosphorylation was increased by β-adrenergic stimulation but not 5′AMP-activated protein kinase activation in human subcutaneous adipose tissue explants, which correlated with lipolysis rates. Our studies suggest that β-adrenergic activation can result in PKA-mediated phosphorylation of ATGL Ser406, to moderately increase ATGL-mediated lipolysis.

scholarly journals Control of Adipose Triglyceride Lipase Action by Serine 517 of Perilipin A Globally Regulates Protein Kinase A-stimulated Lipolysis in Adipocytes

2006 ◽  
Vol 282 (2) ◽  
pp. 996-1002 ◽  
Author(s):  
Hideaki Miyoshi ◽  
James W. Perfield ◽  
Sandra C. Souza ◽  
Wen-Jun Shen ◽  
Hui-Hong Zhang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Adipose Triglyceride Lipase ◽  
Triglyceride Lipase ◽  
Perilipin A ◽  
Kinase A

scholarly journals Hypoxia Restrains Lipid Utilization via Protein Kinase A and Adipose Triglyceride Lipase Downregulation through Hypoxia-Inducible Factor

2018 ◽  
Vol 39 (2) ◽  
Author(s):  
Ji Seul Han ◽  
Jung Hyun Lee ◽  
Jinuk Kong ◽  
Yul Ji ◽  
Jiwon Kim ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Energy Production ◽  
Hypoxia Inducible Factor ◽  
Suppressive Effect ◽  
Adipose Triglyceride Lipase ◽  
Low Oxygen ◽  
Content Type ◽  
Triglyceride Lipase ◽  
Kinase A

ABSTRACT Oxygen is a key molecule for efficient energy production in living organisms. Although aerobic organisms have adaptive processes to survive in low-oxygen environments, it is poorly understood how lipolysis, the first step of energy production from stored lipid metabolites, would be modulated during hypoxia. Here, we demonstrate that fasting-induced lipolysis is downregulated by hypoxia through the hypoxia-inducible factor (HIF) signaling pathway. In Caenorhabditis elegans and mammalian adipocytes, hypoxia suppressed protein kinase A (PKA)-stimulated lipolysis, which is evolutionarily well conserved. During hypoxia, the levels of PKA activity and adipose triglyceride lipase (ATGL) protein were downregulated, resulting in attenuated fasting-induced lipolysis. In worms, HIF stabilization was sufficient to moderate the suppressive effect of hypoxia on lipolysis through ATGL and PKA inhibition. These data suggest that HIF activation under hypoxia plays key roles in the suppression of lipolysis, which might preserve energy resources in both C. elegans and mammalian adipocytes.

Phosphorylation of adipose triglyceride lipase Ser404 is not related to 5′-AMPK activation during moderate-intensity exercise in humans

2012 ◽  
Vol 303 (4) ◽  
pp. E534-E541 ◽  
Author(s):  
Rachael R. Mason ◽  
Ruth C. R. Meex ◽  
Robert Lee-Young ◽  
Benedict J. Canny ◽  
Matthew J. Watt
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Fiber Type ◽  
Venous Blood ◽  
Whole Body ◽  
Moderate Intensity ◽  
Adipose Triglyceride Lipase ◽  
Ampk Activation ◽  
Moderate Intensity Exercise ◽  
Triglyceride Lipase

Intramyocellular triacylglycerol provides fatty acid substrate for ATP generation in contracting muscle. The protein adipose triglyceride lipase (ATGL) is a key regulator of triacylglycerol lipolysis and whole body energy metabolism at rest and during exercise, and ATGL activity is reported to be enhanced by 5′-AMP-activated protein kinase (AMPK)-mediated phosphorylation at Ser406 in mice. This is a curious observation, because AMPK activation reduces lipolysis in several cell types. We investigated whether the phosphorylation of ATGL Ser404 (corresponding to murine Ser406) was increased during exercise in human skeletal muscle and with pharmacological AMPK activation in myotubes in vitro. In human experiments, skeletal muscle and venous blood samples were obtained from recreationally active male subjects before and at 5 and 60 min during exercise. ATGL Ser404 phosphorylation was not increased from rest during exercise, but ATGL Ser404 phosphorylation correlated with myosin heavy chain 1 expression, suggesting a possible fiber type dependency. ATGL Ser404 phosphorylation was not related to increases in AMPK activity, and immunoprecipitation experiments indicated no interaction between AMPK and ATGL. Rather, ATGL Ser404 phosphorylation was associated with protein kinase A (PKA) signaling. ATGL Ser406 phosphorylation in C2C12 myotubes was unaffected by 5-aminoimidazole-4-carboxaminde-1-β-d-ribofuranoside, an AMPK activator, and the PKA activator forskolin. Our results demonstrate that ATGL Ser404 phosphorylation is not increased in mixed skeletal muscle during moderate-intensity exercise and that AMPK does not appear to be an activating kinase for ATGL Ser404/406 in skeletal muscle.

cAMP-positive regulation of angiotensinogen gene expression and protein secretion in rat adipose tissue

2004 ◽  
Vol 286 (3) ◽  
pp. E434-E438 ◽  
Author(s):  
Valérie Serazin ◽  
Marie-Noelle Dieudonné ◽  
Mireille Morot ◽  
Philippe de Mazancourt ◽  
Yves Giudicelli
Keyword(s):  
Adipose Tissue ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Protein Secretion ◽  
Intracellular Camp ◽  
Pathological State ◽  
Mrna Levels ◽  
Adrenergic Stimulation ◽  
Rat Adipose Tissue ◽  
Kinase A

The adipose renin-angiotensin system (RAS) has been assigned to participate in the control of adipose tissue development and in the pathogenesis of obesity-related hypertension. In adipose cells, the biological responses to β-adrenergic stimulation are mediated by an increase in intracellular cAMP. Because cAMP is known to promote adipogenesis and because an association exists between body fat mass, hypertension, and increased sympathetic stimulation, we examined the influence of cAMP on angiotensinogen (ATG) expression and secretion in rat adipose tissue. Exposure of primary cultured differentiated preadipocytes to the cAMP analog 8-bromoadenosine 3′,5′-cyclic monophosphate (8-BrcAMP) or cAMP-stimulating agents (forskolin and IBMX) results in a significant increase in ATG mRNA levels. In adipose tissue fragments, 8-BrcAMP also increases ATG mRNA levels and protein secretion, but not in the presence of the protein kinase A inhibitor H89. The addition of isoproterenol, known to stimulate the synthesis of intracellular cAMP via β-adrenoreceptors, had the same stimulatory effect on ATG expression and secretion. These results indicate that cAMP in vitro upregulates ATG expression and secretion in rat adipose tissue via the protein kinase A-dependent pathway. Further studies are required to determine whether this regulatory pathway is activated in human obesity, where increased sympathetic tone is frequently observed, and to elucidate the importance of adipose ATG to the elevated blood pressure observed in this pathological state.

Positive and negative effects of nitric oxide on Ca2+ sparks: influence of β-adrenergic stimulation

2001 ◽  
Vol 281 (6) ◽  
pp. H2295-H2303 ◽  
Author(s):  
Mark T. Ziolo ◽  
Hideki Katoh ◽  
Donald M. Bers
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Ventricular Myocytes ◽  
Cardiac Contractility ◽  
Adrenergic Stimulation ◽  
High Concentration ◽  
Negative Effects ◽  
Dual Effect ◽  
Kinase A

Nitric oxide (NO) can have a positive or negative effect on cardiac contractility and the ryanodine receptor (RyR). This dual effect has been explained as being dependent on the concentration of NO. We find that cellular RyR response to NO is also dependent on the degree of β-adrenergic stimulation, and thus the state of protein kinase A activation. Ca2+ spark frequency (CaSpF) in rat ventricular myocytes was used as an index of resting RyR activity. CaSpF response to β-adrenergic stimulation was used as an index of protein kinase A activation. High concentration of isoproterenol, a β-adrenergic agonist, caused a large increase in CaSpF; addition of NO (spermine NONOate, 300 μM) then caused a decrease in CaSpF. Low concentration of isoproterenol produced only a slight increase in CaSpF, but the same NO concentration now caused a large increase in CaSpF. A dual effect was also observed in twitch. Thus the net direction of the effects of NO on RyR activity and Ca2+transients (directly or by alteration of sarcoplasmic reticulum Ca2+ load) can be reversed, depending on the ambient level of β-adrenergic activation.

scholarly journals Protein kinase A–dependent modulation of Ca2+ sensitivity in cardiac and fast skeletal muscles after reconstitution with cardiac troponin

2009 ◽  
Vol 133 (6) ◽  
pp. 571-581 ◽  
Author(s):  
Douchi Matsuba ◽  
Takako Terui ◽  
Jin O-Uchi ◽  
Hiroyuki Tanaka ◽  
Takao Ojima ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Cardiac Muscle ◽  
Protein Kinase A ◽  
Striated Muscle ◽  
Physiological Mechanism ◽  
Adrenergic Stimulation ◽  
Fast Skeletal Muscle ◽  
Psoas Muscles ◽  
Kinase A

Protein kinase A (PKA)-dependent phosphorylation of troponin (Tn)I represents a major physiological mechanism during β-adrenergic stimulation in myocardium for the reduction of myofibrillar Ca2+ sensitivity via weakening of the interaction with TnC. By taking advantage of thin filament reconstitution, we directly investigated whether or not PKA-dependent phosphorylation of cardiac TnI (cTnI) decreases Ca2+ sensitivity in different types of muscle: cardiac (porcine ventricular) and fast skeletal (rabbit psoas) muscles. PKA enhanced phosphorylation of cTnI at Ser23/24 in skinned cardiac muscle and decreased Ca2+ sensitivity, of which the effects were confirmed after reconstitution with the cardiac Tn complex (cTn) or the hybrid Tn complex (designated as PCRF; fast skeletal TnT with cTnI and cTnC). Reconstitution of cardiac muscle with the fast skeletal Tn complex (sTn) not only increased Ca2+ sensitivity, but also abolished the Ca2+-desensitizing effect of PKA, supporting the view that the phosphorylation of cTnI, but not that of other myofibrillar proteins, such as myosin-binding protein C, primarily underlies the PKA-induced Ca2+ desensitization in cardiac muscle. Reconstitution of fast skeletal muscle with cTn decreased Ca2+ sensitivity, and PKA further decreased Ca2+ sensitivity, which was almost completely restored to the original level upon subsequent reconstitution with sTn. The essentially same result was obtained when fast skeletal muscle was reconstituted with PCRF. It is therefore suggested that the PKA-dependent phosphorylation or dephosphorylation of cTnI universally modulates Ca2+ sensitivity associated with cTnC in the striated muscle sarcomere, independent of the TnT isoform.

scholarly journals Regulation of Cardiac L-Type Ca 2+ Channel Ca V 1.2 Via the β-Adrenergic-cAMP-Protein Kinase A Pathway

2013 ◽  
Vol 113 (5) ◽  
pp. 617-631 ◽  
Author(s):  
Sharon Weiss ◽  
Shimrit Oz ◽  
Adva Benmocha ◽  
Nathan Dascal
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Adrenergic Receptor ◽  
Transgenic Animals ◽  
Receptor Activation ◽  
Model Systems ◽  
Adrenergic Stimulation ◽  
New Findings ◽  
Kinase A

In the heart, adrenergic stimulation activates the β-adrenergic receptors coupled to the heterotrimeric stimulatory G s protein, followed by subsequent activation of adenylyl cyclase, elevation of cyclic AMP levels, and protein kinase A (PKA) activation. One of the main targets for PKA modulation is the cardiac L-type Ca 2+ channel (Ca V 1.2) located in the plasma membrane and along the T-tubules, which mediates Ca 2+ entry into cardiomyocytes. β-Adrenergic receptor activation increases the Ca 2+ current via Ca V 1.2 channels and is responsible for the positive ionotropic effect of adrenergic stimulation. Despite decades of research, the molecular mechanism underlying this modulation has not been fully resolved. On the contrary, initial reports of identification of key components in this modulation were later refuted using advanced model systems, especially transgenic animals. Some of the cardinal debated issues include details of specific subunits and residues in Ca V 1.2 phosphorylated by PKA, the nature, extent, and role of post-translational processing of Ca V 1.2, and the role of auxiliary proteins (such as A kinase anchoring proteins) involved in PKA regulation. In addition, the previously proposed crucial role of PKA in modulation of unstimulated Ca 2+ current in the absence of β-adrenergic receptor stimulation and in voltage-dependent facilitation of Ca V 1.2 remains uncertain. Full reconstitution of the β-adrenergic receptor signaling pathway in heterologous expression systems remains an unmet challenge. This review summarizes the past and new findings, the mechanisms proposed and later proven, rejected or disputed, and emphasizes the essential issues that remain unresolved.

scholarly journals β-Adrenergic Stimulation Increases Cav3.1 Activity in Cardiac Myocytes through Protein Kinase A

PLoS ONE ◽  
2012 ◽  
Vol 7 (7) ◽  
pp. e39965 ◽  
Author(s):  
Yingxin Li ◽  
Fang Wang ◽  
Xiaoying Zhang ◽  
Zhao Qi ◽  
Mingxin Tang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Cardiac Myocytes ◽  
Adrenergic Stimulation ◽  
Kinase A

scholarly journals NMR Structural/Functional Characterization of an Oncogenic Mutant of cAMP-Dependent Protein Kinase A: PRKACA-DNAJB1

2016 ◽  
Vol 110 (3) ◽  
pp. 47a
Author(s):  
Adak N. Karamafrooz ◽  
Jonggul Kim ◽  
Geoffrey Li ◽  
Sanford M. Simon ◽  
Susan S. Taylor ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Functional Characterization ◽  
Dependent Protein Kinase ◽  
Camp Dependent Protein Kinase ◽  
Dependent Protein ◽  
Kinase A
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