AMP-activated protein kinase activation

Beauloye, C., Marsin, A. S., Bertrand, L., Krause, U., Hardie, D. G., Vanoverschelde, J. L., and Hue, L. 2001. Insulin antagonizes AMP-activated protein kinase activation by ischemia or anoxia in rat hearts, without affecting total adenine nucleotides. FEBS Lett 505(3) 348-352. 

Kudo, N., Gillespie, J. G., Kung, L., Witters, L. A., Schulz, R., Qanachan, A. S., and Lopaschuk, G. D. 1996. Characterization of 5 AMP-activated protein kinase activity in the heart and its role in inhibiting acetyl-CoA carboxylase during reperfusion following ischemia. Biochim Biophys Acta 1301 67-75. 

Tomas, E., Tsao, T. S., Saha, A. K., Murrey, H. E., Zhang, C. C., Itani, S. I., Lodish, H. F., and Ruderman, N. B. 2002. Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci USA 99 16309-16313. 

Wang, W., Yang, X., Lopez de Silanes, I., Carling, D., and Gorospe, M. 2003. Increased AMP ATP ratio and AMP-activated protein kinase activity during cellular senescence linked to reduced HuR function. J Biol Chem 278 27016-27023. 

ACC-2 produces malonyl CoA, which inhibits carnitine palmitoyl transferase I, thereby blocking fatty acid entry into the mitochondria. Muscle also contains malonyl CoA decarboxylase, which catalyzes the conversion of malonyl CoA to acetyl CoA and carbon dioxide. Thus, both the synthesis and degradation of malonyl CoA is carefully regulated in muscle cells to balance glucose and fatty acid oxidation. Both allosteric and covalent means of regulation are employed. Citrate activates ACC-2, and phosphorylation of ACC-2 by the adenosine monophosphate (AMP)-activated protein kinase inhibits ACC-2 activity. Phosphorylation of malonyl CoA decarboxylase by the AMP-activated protein kinase activates the enzyme, further enhancing fatty acid oxidation when energy levels are low. 

Musi, N. Hayashi, T. Fujii, N. Hirshman, M.F. Witters, L.A. Goodyear, L.J. AMP-activated protein kinase activity and glucose uptake in rat skeletal muscle. Am. J. Physiol., 280, E677-684 (2001)... 

Zou, M. H., and Y. Wu. 2008. AMP-activated protein kinase activation as a strategy for protecting vascular endothelial function. Clin Exn Pharmacol Phvsiol 35 (5-6) 535-45. 

Reznick RM, Zong H, Morino K et al. (2007) Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis. Cell Metab 5, 151-156. 

Frosig, C., Jorgensen, S.B., Hardie, D.G., Richter, E.A., and Wojtaszewski, J.E, 5 -AMP-activated protein kinase activity and protein expression are regulated by endurance training in human skeletal muscle. Am J Physiol Endocrinol Metab, 286, E411, 2004. 

Fujii, N., T. Hayashi, M.F. Hirshman, IT. Smith, S.A. Habinowski, L. Kaijser, J. Mu, O. Ljungqvist, M.J. Bimbaun, L. A. Witters, A. Thorell and L.J. Goodyear, 2000. Exercise induces isoform-speoific increase in 5 AMP-activated protein kinase activity in human skeletal muscle. Biochem. Biophys. Res. Commun. 273, 1150-1155. 

A number of kinase structures have been determined in various catalytic states. For example, structures of the cyclin-dependent kinase, CDK2, in its inactive state and in a partially active state after cyclin binding have been discussed in Chapter 6. The most thoroughly studied kinase is the cyclic AMP-dependent protein kinase the structure of both the inactive and the active... 

Cyclic AMP-dependent protein kinase is shown complexed with a pseudosubstrate peptide (red). This complex also includes ATP (yellow) and two Mn ions (violet) bound at the active site. 

FIGURE 15.7 Cyclic AMP-dependent protein kinase (also known as PKA) is a 150- to l70-kD R9C9 tetramer in mammalian cells. The two R (regulatory) subunits bind cAMP ( = 3 X 10 M) cAMP binding releases the R subunits from the C (catalytic) subunits. C subunits are enzymatically active as monomers. 

Group II assays consist of those monitoring cellular second messengers. Thus, activation of receptors to cause Gs-protein activation of adenylate cyclase will lead to elevation of cytosolic or extracellularly secreted cyclic AMP. This second messenger phosphorylates numerous cyclic AMP-dependent protein kinases, which go on to phosphorylate metabolic enzymes and transport and regulatory proteins (see Chapter 2). Cyclic AMP can be detected either radiometrically or with fluorescent probe technology. 

Protein kinase A (PKA) is a cyclic AMP-dependent protein kinase, a member of a family of protein kinases that are activated by binding of cAMP to their two regulatory subunits, which results in the release of two active catalytic subunits. Targets of PKA include L-type calcium channels (the relevant subunit and site of phosphorylation is still uncertain), phospholam-ban (the regulator of the sarcoplasmic calcium ATPase, SERCA) and key enzymes of glucose and lipid metabolism. 

FIGURE 14-6 Main signaling pathways for histamine receptors. Histamine can couple to a variety of G-protein-linked signal transduction pathways via its four different receptors. The Hj receptor activates the phosphatidylinositol turnover via Gq/11 proteins. The other receptors either positively (H2 receptor) or negatively (H3 and H4 receptor) regulate adenylyl cyclase activity via Gs and GUo protein activation respectively. Several additional signaling pathways have been described, which are not shown. Abbreviations PfP2, phosphatidylinositol 4,5-bisphosphate PIC, phospholipase C AC, adenylyl cyclase ATP, adenosine triphosphate cAMP, cyclic AMP PKC, protein kinase C PICA, protein kinase A. 

Timchalk C, Charles AK. 1986. Differential effects of carcinogens on hepatic cytosolic cyclic AMP-dependent protein kinase activity. J Am Coll Toxicol 5(4) 267-273. 

Adrenaline increases the rate of gluconeogenesis it binds to the a-receptor on the surface of the liver cell, which results in an increase in cytosolic concentration of Ca " ions (Chapter 12). This increases the activity of the Ca " -catmodulin-dependent protein kinase which phosphory-lates and causes similar changes in the activities of the enzymes PFK-2 and pyruvate kinase to those resulting from activation of cyclic-AMP-dependent protein kinase. Hence Ca " ions increase the rate of gluconeogenesis. 

Figure 7.15 Inhibition of acetyl-CoA carboxylase by cyclic AMP dependent protein kinase and AMP dependent protein kinase the dual effect of glucagon. Phosphorylation of acetyl-CoA carboxylase by either or both enzymes inactivates the enzyme which leads to a decrease in concentration of malonyl-CoA, and hence an increase in activity of carnitine palmitoyltransferase-I and hence an increase in fatty acid oxidation. Insulin decreases the cyclic AMP concentration maintaining an active carboxylase and a high level of malonyl-CoA to inhibit fatty acid oxidation.

It is instructive to note that the biochemistry of the reactions that initiate the visual cascade and the glycogenolytic cascade is similar. The cyclic AMP-dependent protein kinase complex comprises the regulatory and catalytic components (R and C) for which the regulatory signal is the concentration of cyclic AMP. This binds to the regulatory component of the kinase (the R subunit) which then dissociates from the R-C complex. The C is now catalyti-cally active and catalyses the initial reaction in a cascade sequence which leads to activation of the target protein (phosphorylase). 

The self-phosphorylation process catalyzed by many protein kinases as part of the regulatory mechanism for their own activation. Because true autophosphorylation is a unimolecular reaction involving enzyme both as catalyst and phosphoryl acceptor, the fraction of autophosphory-lated enzyme at any time after addition of ATP (or another phosphoryl donor) will be independent of the initial concentration of the enzyme. This criterion was first applied to the autophosphorylation of cardiac muscle cyclic AMP-stimulated protein kinase, now designated protein kinase A (PKA). At a fixed concentration of MgATP , the fraction of autophosphorylated protein will follow the first-order rate laws, [A]/[A ] where k is a first-order rate constant. 

Figure 14-2. Regulation of cyclic AMP-dependent protein kinase A (PKA) by cyclic AMP. Activation of adenylate cyclase by binding of G( -GTP amplifies the signal by synthesis of many molecules of cyclic AMP. Cyclic AMP binding to PKA causes dissociation of the regulatory subunits from the catalytic subunits, which carry on the signal. Phosphodiesterase regulates the concentration of cyclic AMP by catalyzing its hydrolysis to AMP, which shuts off the signal.

Roberson E, Sweat JD (1996) Transient activation of cyclic AMP-dependent protein kinase dming hippocampal long-term potentiation. J Biol Chem 271 30436-30441 Rodrigues S, Schafe GE, LeDoux JE (2001) Intra-amygdala blockade of the NR2B subimit of the NMDA receptor disrupts the acquisition but not the expression of fear conditioning. J Neurosci 21 6889-6896... 

AMP/intracellular mediator fm many diffo-ent hormones, communicating the signal 1 activating the cyclic AMP-dependait protein kinase... 

Lent, B.A. Kim, K.-H. Phosphorylation and activation of acetyl-coenzyme A Carboxylase kinase by the catalytic subunit of cyclic AMP-dependent protein kinase. Arch. Biochem. Biophys., 225, 972-978 (1983)... 

Hormonal control of the activity of phosphorylase kinase. Just as the activity of phosphorylase is increased by phosphorylation, so is the activity of its phosphorylase kinase (which may be phosphorylated on two serine residues, one in an a subunit and one in a /3 subunit). Hormonal stimulation (/3-adrenergic) leads to the production of 3, 5 -cyclic AMP ( second messenger ), which stimulates the activity of the cyclic-AMP-dependent protein kinase that catalyzes the phosphorylation of phosphorylase kinase. 

The yeast enzyme is a homodimer of Mr2 X 102 500 and has 49% sequence identity to the muscle enzyme. The yeast enzyme is more simply regulated feedback inhibition by the allosteric inhibitor glucose-6-phosphate and activation by a 3 -5 -cyclic AMP-dependent protein kinase or a yeast phosphorylase that phosphorylates Thr-10.55... 

As mentioned in the introduction, CaMKKs can phosphorylate proteins in addition to CaMKI and CaMKIV. One such alternate target is the AMP-dependent protein kinase (AMPK) (Hawley et al., 1995 Hamilton et al., 2002), and recent studies present compelling evidence that CaMKKs are physiologically relevant activators of AMPK in cultured cells. These studies are of particular interest as AMPK is a kinase intimately involved in the regulation of metabolism, both at the cellular and organismal levels (Kemp et al., 1999). In mammals, AMPK has been implicated in diabetes, obesity and cardiovascular disease (Arad et al., 2002 Kemp et al., 2003) prompting a flurry of studies to identify the relevant AMPKK involved in each tissue that participates in the etiology of these diseases. 

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