5 -AMP-dependent protein kinase

Further processes involving AMPK include phosphorylation of creatine kinase (GK) (P-CK being less active and thus maximizing ATP levels for immediate use) phosphorylation of hydroxymethylglutarylCoA reductase (ElMGGoAR) (P-ElMGCoAR being inhibited 

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Taylor, S. S., Radzio-Andzelm, E. Cyclic AMP-dependent protein kinase. In Protein Kinases, Woodgett, J. R., editor, IRL Press, Oxford, 1994. 

Steinberg, R. A. A kinase-negative mutant of s49 mouse lymphoma cells is defective in posttranslational maturation of catalytic subunitof cyclic amp-dependent protein kinase. Mol. Cell Biol. 11 (1991) 705-712. 

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. 

Earner, J., 1990. Insulin and the stimulation of glycogen synthesis The road from glycogen structure to glycogen synthase to cyclic AMP-dependent protein kinase to insulin mediators. Advances in Enzymology 63 173-231. 

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. 

AKAPs are cyclic AMP-dependent protein kinase (PKA)-anchoring proteins, a family of about 30 proteins anchoring PKA at subcellular sites in close vicinity to a certain substrate. 

Cyclic nucleotides (cAMP and cGMP) are formed enzymatically from the corresponding triphosphates. As ubiquitous second messengers, they mediate many cellular functions which are initiated by first (extracellular) messengers. Their prime targets in eucaryotic cells are protein kinases ( cyclic AMP-dependent protein kinase, cyclic GMP-dependent protein kinase), ion channels and ensymes. 

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. 

Sharma, R. and Wang, J. H. Differential regulation of bovine brain calmodulin-dependent cyclic nucleotide phosphodiesterase isozzymesdby cyclic AMP-dependent protein kinase and calmodulin-dependent protein phosphatase. Proc. Natl Acad. Sci. U.S.A. 82 2603-2607,1986. 

Couve, A., Thomas, P, Calver, A. R., et al. (2002) Cyclic AMP-dependent protein kinase phosphorylation facilitates GABAb receptor-effector coupling. Nat. Neurosci. 25,25. 

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. 

PKA (A kinase) c AMP-dependent protein kinase cAMP Energy signaling (low energy signal)... 

Roth, N. S., Campbell, P. T., Caron, M. G., Lefkowitz, R. J., and Lohse, M. J. (1991) Comparative rates of desensitization of beta-adrenergic receptors by the beta-adrenergic receptor kinase and the cyclic AMP-dependent protein kinase. Proc. Natl. Acad. Sci. U. S. A. 88, 6201-6204. 

Cyclic AMP-dependent protein kinase (protein kinase-A). 

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). 

Figure 3.5. Aminoglycoside kinases are members of the protein kinase family. Comparison of c-AMP-dependent protein kinase (cAPK) to APH(3 )-IIa and APH(3 )-IIIa. (A) cAPK (catalytic domain) from Mus musculus (pdb ID 2CPK). (B) APH(3 )-IIa from Klebsiella pneumoniae (pdb ID 1ND4). (C) APH(3 )-IIIa from Enterococcus faecalis (pdb ID 1L8T).

Chambers TC, Pohl J, Glass DB, Kuo JF (1994) Phosphorylation by protein kinase C and cyclic AMP-dependent protein kinase of synthetic peptides derived firom the linker region of human P-glycoprotein. Biochem J 299 309-315... 

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... 

Cyclic AMP (adenosine 3, 5 -cyclic monophosphate) is anotter secondary messenger that acts as an intracellular mediator for many different hormones, communicating the signal through the cyclic AMP-dependent protein kinase. This, in turn, phosphorylates other proteins at ine and threonine residues. Certain cell-surfece receptors act by increasing the concentration of intracellular cyclic AMP. A long-duration sudden increase of intracellular cyclic AMP takes place with cholera toxins in intestinal epithelial cells. Other cell-surfece receptors play the opposite role of decreasing the concentration of cyclic AMP. 

Nemeroff CB, Krishnan KRR, Reed D, et al Adrenal gland enlargement in major depression a computed tomographic study. Arch Gen Psychiatry 49 384-387, 1992 Nestler EJ, Terwilliger RZ, Duman RS Chronic antidepressant administration alters the subcellular distribution of cyclic AMP-dependent protein kinase in rat frontal cortex. J Neurochem 53 1644-1647, 1989 Nestor PC, Parasuraman R, Haxby JV, et al Divided attention and metabolic brain dysfunction in mild dementia of the Alzheimer s type. Neuropsychologia 29(5) 379-387, 1991... 

Bredt, D. S., Ferris, C. D., and Snyder, S. H. (1992). Nitric oxide synthase regulatory sites. Phosphorylation by cyclic AMP-dependent protein kinase, protein kinase C, and calcium/calmodulin protein kinase identification of flavin and calmodulin binding sites. . Biol. Chem. 267, 10976-10981. 

Higashi, K. Fukunaga, K. Matsui, K. Maeyama, M. Miyamoto, E. Purification and characterization of myosin light-chain kinase from porcine myometrium and its phosphorylation and modulation by cyclic AMP-dependent protein kinase. Biochim. Biophys. Acta, 747, 232-240 (1983)... 

Moffett, S. Rousseau, G. Lagace, M. Bouvier, M. The palmitoylation state of the 2-adrenergic receptor regulates the synergistic action of cyclic AMP-dependent protein kinase and )8-adrenergic receptor kinase involved in its phosphorylation and desensitization. J. Neurochem., 76, 269-279 (2001)... 

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