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PubMed1994

[Five cases of phosphorylase b kinase deficiency affecting muscle or liver: clinical symptoms and diagnosis].

Muscle, erythrocyte and/or leukocyte phosphorylase b kinase (PBK) activities were measured in 5 patients and in 2 families. The relation between phenotype and enzyme deficiency in clinically variable samples based on measurement of erythrocytes, leukocytes or muscle was described. Three patients showed the enzyme deficiency in liver and the disease was transmitted as an X-linked recessive trait. In these cases, our results suggested that carrier detection was more reliable with erythrocytes than leukocytes. Two patients showed enzyme deficiency in muscle, and the mode of inheritance was not clear. In these cases, muscle biopsies were necessary for diagnosis.

Child↗
PubMed1989

Ca2+-dependent and cAMP-dependent control of nicotinic acetylcholine receptor phosphorylation in muscle cells.

Mouse BC3H1 myocytes were incubated with 32Pi before acetylcholine receptors were solubilized, immunoprecipitated, and subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis. More than 90% of the 32P found in the receptor was bound to the delta subunit. Two phosphorylation sites in this subunit were resolved by reverse phase high performance liquid chromatography after exhaustive proteolysis of the protein with trypsin. Sites 1 and 2 were phosphorylated to approximately the same level in control cells. The divalent cation ionophore, A23187, increased 32P in site 1 by 40%, but did not affect the 32P content of site 2. In contrast, isoproterenol increased 32P in site 2 by more than 60%, while increasing 32P in site 1 by only 20%. When dephosphorylated receptor was incubated with [gamma-32P]ATP and the catalytic subunit of cAMP-dependent protein kinase, the delta subunit was phosphorylated to a maximal level of 1.6 phosphates/subunit. Approximately half of the phosphate went into site 2, with the remainder going into a site not phosphorylated in cells. The alpha subunit was phosphorylated more slowly, but phosphorylation of both alpha and delta subunits was blocked by the heat-stable protein inhibitor of cAMP-dependent protein kinase. Phosphorylation of the receptor was also observed with preparations of phosphorylase kinase. In this case phosphorylation occurred in the beta subunit and site 1 of the delta subunit, neither of which were phosphorylated by cAMP-dependent protein kinase. The rate of receptor phosphorylation by phosphorylase kinase was slow relative to that catalyzed by cAMP-dependent protein kinase. Therefore, it can not yet be concluded that phosphorylase kinase phosphorylates the beta subunit and the delta subunit site 1 in cells. However, the results strongly support the hypothesis that phosphorylation by cAMP-dependent protein kinase accounts for phosphorylation of the alpha subunit and the delta subunit site 2 in response to elevations in cAMP.

Amino Acids↗
PubMed1986

Adult muscle phosphorylase "b" kinase deficiency.

A 35-year-old man had severe exercise intolerance and cramps. Venous blood lactate did not rise after ischemic exercise, and electromyographically silent contracture of hand muscles appeared. Histochemistry and electronmicroscopy of a muscle biopsy revealed subsarcolemmal and intermyofibrillar accumulation of glycogen. Biochemical studies showed moderately increased amount of glycogen. Total phosphorylase activity was normal, but the active form "a" was 27% of normal. Phosphorylase kinase activity was 12% of the normal value and was normal in leukocytes and erythrocytes.

Adult↗
PubMed1980

Isolation and characterization of cyclic AMP-independent glycogen synthase kinase from rat skeletal muscle.

Glycogen synthase kinase was isolated from rat skeletal muscle. This kinase, which is cyclic nucleotide-independent and calcium-independent, was separated from phosphorylase kinase, cyclic AMP-dependent protein kinase and phosvitin kinase by phosphocellulose chromatography. Gel filtration on Sephadex G-100 resolved the glycogen synthase kinase into two fractions with apparent molecular weights of 68 000 (peak I) and 52 000 (peak II). This step also separated glycogen synthase kinase from the catalytic subunit of the cyclic AMP-dependent protein kinase, which had an apparent molecular weight of 39 000. Peak II glycogen synthase kinase activity was not affected by the addition of calcium, EGTA or a number of cyclic nucleotides. In addition to ATP, dATP would serve as the phosphate donor. Other trinucleotides tested were either poor or ineffective substrates. Activity was about 5-fold greater with Mg2+ than with Mn2+. Glycogen stimulated activity about 25%. Modifications of the methods of Soderling et al. ((1970) J. Biol. Chem. 245, 6317--6328) and Nimmo et al. ((1976) Eur. J. Biochem. 68, 21--30) were developed for purification of glycogen synthease (UDPglucose:glycogen 4-alpha D-glucosyltransferase, EC 2.4.1.11) to specific activity of 35 units/mg of protein. Using this preparation of glycogen synthase as substrate, the phosphorylation and inactivation catalyzed by glycogen synthase kinase was compared to that catalyzed by cyclic AMP-dependent protein kinase or phosphorylase kinase. Each of the kinases had different specificities for phosphorylation sites on glycogen synthase.

Animals↗
PubMed1999

Regulation of glycogen utilization in ischemic hearts after 24 hours of fasting.

INTRODUCTION: Fasting protects the ischemic heart from injury and infarction. Previous studies have shown that hearts from fasted animals have greater glycogen utilization and a lower cytosolic redox state (NADH/NAD+) during global ischemia. While the mechanisms of increased glycogen utilization in fasted animals have not been elucidated, animals that hibernate or are tolerant of anoxia are known to increase the tissue content of the active form of glycogen phosphorylase, phosphorylase a. Therefore, this study was designed to (a) determine whether hearts from fasted animals have increased activity of glycogen phosphorylase during ischemia and (b) define those mechanisms responsible for this increase. METHODS: Hearts isolated from either fed or fasted (24 h) rats were perfused and freeze-clamped at baseline, and after 1 and 10 min of ischemia, for measurement of phosphorylase activity, phosphorylase kinase activity, and glucose-6-phosphate concentrations. RESULTS: Fasting increased the phosphorylase a/b ratio under both baseline and ischemic conditions. This increase was not accompanied by an increase in the activity of phosphorylase kinase, either with maximal [Ca2+] or under physiologic [Ca2+]. Glucose 6-phosphate concentrations were lower in hearts from fasted animals under baseline, but not ischemic, conditions. CONCLUSIONS: Fasting enhances glycogen utilization during ischemia by increasing the active form of glycogen phosphorylase. This increase is not due to a change in phosphorylation by phosphorylase kinase nor end-product inhibition by G-6P. While the precise mechanism of increased glycogen phosphorylase activity in fasted animals is not clear, one likely explanation may be the lower cytosolic redox state demonstrated in the myocardium of fasted animals.

Analysis of Variance↗
PubMed1989

Phosphorylase b kinase deficiency in a boy with glycogenosis affecting both liver and muscle.

A boy with marked hepatomegaly and motor weakness was investigated for glycogen storage disease. Glycogen accumulation was demonstrated in both liver and muscle and there was a deficiency of phosphorylase b kinase activity. On the basis of biochemical findings, an autosomal recessive mode of inheritance was considered likely, rather than the more common X-linked variant, with primarily liver involvement.

Child↗
PubMed1984

Homology of the gamma subunit of phosphorylase b kinase with cAMP-dependent protein kinase.

The complete amino acid sequence of the catalytic subunit (gamma subunit) of rabbit skeletal muscle phosphorylase b kinase was determined. The gamma subunit was purified by gel filtration in acidic 8 M urea after reduction and S-carboxymethylation in 7 M guanidine hydrochloride. Cleavage of the gamma subunit at arginyl bonds gave a complete set of nonoverlapping peptides. Overlapping peptides were obtained by cleavage at methionyl, tryptophanyl, or glutamyl bonds and by selected subdigestion of two large peptides obtained by cleavage at methionyl bonds. Sequence analysis established that the protein contains 386 residues corresponding to a molecular weight (Mr) of 44673. Comparison of the gamma subunit with the catalytic subunit of bovine cAMP-dependent protein kinase and with tyrosine-specific kinases of viral origin revealed a significant degree of sequence identity among all of these proteins. These data suggest that calcium-dependent protein kinases may share a common ancestral gene and a common structural basis for catalytic function with a wide variety of other protein kinases which respond to different signals and control quite different processes.

Amino Acid Sequence↗
PubMed1987

Transient activation of cyclic AMP-dependent protein kinase and phosphorylase during the cardiac cycle in the canine myocardium in situ and the effect of propranolol.

The activity ratio of cyclic AMP-dependent protein kinase and glycogen phosphorylase were determined at various stages of the contraction cycle in the canine heart in situ. Both activity ratios vary transiently throughout the contraction-relaxation cycle, the higher values occurring during systole. The rise in the activity ratio of protein kinase was found to coincide with the maximum in the level of cyclic AMP. Propranolol pretreatment prevents the transient in the level of the nucleotide as well as in the activity ratio of the kinase indicating i) a causal relationship between these changes and ii) a neurohumoral, beat-to-beat regulation by catecholamines. Contrary the activity ratio of phosphorylase retains, in the presence of propranolol, its transient changes during the cardiac cycle, probably caused by a Ca2+-mediated activation of phosphorylase kinase during the contraction process.

Animals↗
PubMed1989

Insulin stimulates dephosphorylation of phosphorylase in rat epitrochlearis muscles.

We have investigated the effects of insulin on the phosphorylation of glycogen phosphorylase in skeletal muscle. Rat epitrochlearis muscles were incubated in vitro with 32Pi to label cellular phosphoproteins, before being treated with hormones. Phosphorylase, phosphorylase kinase, and glycogen synthase were immunoprecipitated under conditions that prevented changes in their phosphorylation states. Based on measurements of the activity ratio (-AMP/+AMP) and the 32P content of phosphorylase, 4-8% of the phosphorylase in untreated muscles appeared to be phosphorylated. Epinephrine promoted increases of approximately 4-fold in the 32P content and activity ratio. Neither these effects nor the epinephrine-stimulated increases in phosphorylation of glycogen synthase and phosphorylase kinase were attenuated by insulin. However, insulin at physiological concentrations rapidly decreased the 32P content of phosphorylase in muscles incubated without epinephrine. Results from peptide mapping experiments indicate that phosphorylase was phosphorylated at a single site in both control and insulin on phosphorylase represented a decrease in 32P of approximately 50%. By comparison, the 32P content of glycogen synthase and the beta subunit of phosphorylase kinase were decreased by only 20 and 16%, respectively; the 32P content of the kinase alpha subunit was not affected by insulin. The results provide direct evidence that insulin decreases the amount of phosphate in phosphorylase and phosphorylase kinase. These findings have important implications with respect to both the regulation of glycogen metabolism in skeletal muscle and the mechanism of insulin action.

Animals↗
PubMed1970

ATP-dependent and cyclic AMP-dependent activation of rat adipose tissue lipase by protein kinase from rabbit skeletal muscle.

Brief incubation of partially purified preparations of hormone-sensitive lipase from rat epididymal fat pads with ATP, Mg(++), cyclic adenosine 3':5'-monophosphate and rabbit muscle protein kinase (phosphorylase b kinase kinase) resulted in enhancement of lipolytic activity (44-93%). Little or no activation was observed when either the cofactor mixture or the protein kinase was omitted. When the fat pads were incubated with epinephrine prior to homogenization, addition of kinase and cofactors to the soluble supernatant fraction caused no activation whereas good activation was obtained in preparations from paired fat pads not exposed to epinephrine. The results indicate that the cyclic AMP-mediated activation of hormone-sensitive lipase in adipose tissue involves a protein phosphorylation step. Whether the lipase itself is phosphorylated and thus activated or whether the protein kinase is activating a mediating enzyme, in analogy with its action in the glycogen phosphorylase system, remains to be determined.

Adenine Nucleotides↗
PubMed1990

Myopathic evolution of an exertional muscle pain syndrome with phosphorylase b kinase deficiency.

The symptoms of a myopathy permanently affecting limb girdle muscles are reported in a 31-year-old woman who has been presenting an exertional muscle pain syndrome with myoglobinuria for 20 years. Investigations revealed a slightly decreased utilization of glycogen in muscle, while its storage affected only rare type 2 fibers. Active phosphorylase was undetectable and phosphorylase b kinase activity was clearly decreased in muscle cells, but normal in erythocytes, lymphocytes and cultured fibroblasts.

Adult↗
PubMed1975

Enzymes regulating glycogen metabolism in swine subcutaneous adipose tissue. I. Phosphorylase and phosphorylase phosphatase.

Glycogen phosphorylase from swine adipose tissue was purified nearly 700-fold using ethanol precipitation, DEAE-cellulose adsorption, AMP-agarose affinity chromatography, and agarose gel filtration. The purified enzyme migrated as one major and several minor components during polyacrylamide gel electrophoresis. Activity was associated with the major component and at least one of the minor components. The molecular weight of the disaggregated, reduced, and alkylated enzyme, estimated by polyacrylamide gel electrophoresis performed in the presence of sodium dodecyl sulfate, was 90,000. Stability of the purified enzyme was considerably increased in the presence of AMP. The isoelectric pH of the enzyme in crude homogenates was 6.3. The sedimentation coefficient of the purified enzyme (7.9 S) and that in crude homogenates (7.3 S) was determined by sucrose density gradient sedimentation. Optimal pH for activity was between pH 6.5 and 7.1. Apparent Km values for glycogen and inorganic phosphate were 0.9 mg/ml and 6.6 mM, respectively. The Ka for AMP was 0.21 mM. Enzyme activity was increased by K2SO4, KF, KCl, and MgCl2 and decreased by NaCl, Na2SO4, D-glucose, and ATP. Inhibition by glucose was noncompetitive with the activator AMP; inhibition by ATP was partially competitive with AMP. The purified enzyme was activated by incubation with skeletal muscle phosphorylase kinase. Enzyme in crude homogenates was activated by the addition of MgCl2 and ATP; activation was not blocked by addition of protein kinase inhibitor, suggesting that phosphorylase kinase in homogenates of swine adipose tissue is present largely in an activated form. Deactivation of phosphorylase a by phosphorylase phosphatase was studied using enzyme purified approximately 200-fold from swine adipose tissue by ethanol precipitation, DEAE-cellulose chromatography, and gel filtration. The Km of the adipose tissue phosphatase for skeletal muscle phosphorylase a was 6 muM. The purified swine adipose tissue phosphorylase, labeled with 32-P, was inactivated and dephosphorylated by the adipose tissue phosphatase. Dephosphorylation of both skeletal muscle and adipose tissue substrates was inhibited by AMP and glucose reversed this inhibition. Several lines of evidence suggest that AMP inhibition was due to an action on the substrate rather than on the enzyme. We have previously reported that the system for phosphorylase activation in rat fat cells differs in some important characteristics from that in skeletal muscle. However, both swine fat phosphorylase and phosphorylase phosphatase have major properties very similar to those described for the enzymes from skeletal muscle.

Adenosine Monophosphate↗
PubMed1996

Genetic deficiencies of the glycogen phosphorylase system.

Several types of glycogen storage disease attributable to a deficiency of phosphorylase or phosphorylase kinase have been described. These diseases have been divided according to clinical symptoms, mode of inheritance, and affected tissue. However, this classification is questionable, as the clinical symptoms of these different diseases are similar, the mode of inheritance is often difficult to establish, and the biochemical assays are subject to several technical problems. A better classification would be based upon the identification of mutations in the respective disease genes. The molecular heterogeneity, however, is large, and at least 10 genes are involved. Mutations have been found in the muscle phosphorylase gene in patients with muscle phosphorylase deficiency, in the gene encoding the liver alpha subunit of phosphorylase kinase in patients with X-linked liver glycogenosis, and in the gene for the muscle alpha subunit of phosphorylase kinase in a patient with muscle phosphorylase kinase deficiency. We review here the different deficiencies of the phosphorylase system.

Genes, Recessive↗
PubMed1989

The Albert Lasker Medical Awards. Role of the cyclic AMP-dependent protein kinase in signal transduction.

The first example of an enzyme that undergoes phosphorylation and dephosphorylation was phosphorylase, which catalyzes the initial step in the breakdown of tissue glycogen, a process that occurs when cells are stimulated by certain hormones. The phosphorylation reaction that activates phosphorylase is catalyzed by an enzyme designated "phosphorylase kinase," whereas the dephosphorylation reaction is catalyzed by an enzyme called "phosphorylase phosphatase." Phosphorylase kinase, like phosphorylase itself, is regulated by phosphorylation-dephosphorylation. In this instance the enzyme is phosphorylated and activated by a protein kinase that is the intracellular target of adenosine 3',5'-cyclic phosphate, the second messenger of hormone action that was discovered by the late Earl Sutherland. Knowledge of these steps led to the establishment of the glycogenolytic cascade in which adenosine 3',5'-cyclic phosphate, formed as a result of hormone action, first activates the adenosine 3',5'-cyclic phosphate-dependent protein kinase, which in turn activates phosphorylase kinase, which then converts inactive phosphorylase to its active form. This is followed by the breakdown of glycogen.

Animals↗
PubMed1989

Phosphorylase a formation in protein-glycogen particles isolated from fast-twitch muscle of euthyroid and hypothyroid rats.

A fraction containing a protein-glycogen complex was isolated from rat skeletal muscle in order to study the effect of hypothyroidism on phosphorylase activation in this structural and functional unit of the glycogenolytic process. The total activities of phosphorylase and phosphorylase phosphatase in euthyroids and hypothyroids were the same in the fraction containing the protein-glycogen complex (P2 suspension). Hypothyroidism selectively lowered the maximal phosphorylase kinase activity in glycogen particles in the P2 suspension by 40%. Addition of Mg2+ (10 mM), ATP (2 mM), and Ca2+ (5 mM) rapidly stimulated phosphorylase b to a conversion resulting from phosphorylase kinase activation. Hypothyroidism reduced the rate of phosphorylase a formation by 50-70% in the P2 suspension. Glucose 6-phosphate (0.4-1.4 mM) inhibited the rate of phosphorylase a formation and this inhibition was similar for eu- and hypothyroids. There was a shift from 5.2 to 5.8 in the free Ca2+ concentration (pCaF) for half-maximal activation of phosphorylase in the P2 suspension of hypothyroids. A sixfold higher steady-state level of phosphorylase in euthyroids compared to hypothyroids was observed at a pCaF of 5.5. The Ca2+ sensitivity of the phosphorylase kinase, however, was not changed by hypothyroidism. These results provide further insight into the different time course of the phosphorylase activation in skeletal muscle during tetanic stimulation observed in euthyroidism and hypothyroidism (W. J. Leijendekker et al. (1985) Metabolism 34, 437-441).

Animals↗
PubMed1998

Infantile muscle phosphorylase-b-kinase deficiency. A case report.

A Turkish girl is described who showed a severe floppy infant syndrome and respiratory failure at birth. She suffered upper respiratory tract infections and pneumonia. She was ventilated and had hypercapnoea secondary to bradypnoea. Biochemical analysis of skeletal muscle revealed a slightly increased glycogen content, and enzymatic analysis revealed a muscle phosphorylase-b-kinase deficiency. The infant succumbed after 140 days due to persistent apnoea and asystole. Isolated muscle phosphorylase-b-kinase deficiency should be considered as a possible diagnosis in floppy infants.

Brain Diseases, Metabolic↗