Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myotonic dystrophy (DM) is an adult form of muscular dystrophy affecting about 1 in 8,000 individuals in most populations. Although common symptoms include progressive muscle weakness and stiffness, it is characterised by a heterogeneous clinical picture. Despite this variation in both the nature and severity of the symptoms seen in affected individuals, DM is genetically homogeneous, segregating as a single locus on the proximal long arm of human chromosome 19. As the biochemical abnormality underlying the disease was unknown, a reverse genetics (or positional cloning) strategy for identifying the gene responsible was adopted. The resulting collaborative effort culminated in the detection of the molecular mutation event and the gene within which it lies: the expansion of a trinucleotide repeat (CTG) at the 3' end of a gene encoding a member of the cyclic AMP-dependent protein kinase family. This has diagnostic implications since an easy, reliable and predictive test can now be offered to individuals with a family history of DM. These findings are also a prerequisite for further studies concerning the biochemical and physiological aetiology of DM and possible therapeutic strategies. In addition, the striking similarity between findings at the DNA level in DM and those in fragile X syndrome and spinal and bulbar muscular atrophy suggests that the mechanism leading to the increase in copy number of trinucleotide repeats at particular loci may be responsible for a number of other genetic diseases.
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PMID:Myotonic dystrophy: another case of too many repeats? 130 24

Focal degenerative changes of skeletal muscle fibers (decrease in mean diameter, excessive axonal branching and a decrease in the mean diameter of motor end-plates together with a reduction of their acetylcholinesterase levels) were found by means of the experimental model thyrotoxic myopathy in mice compared to controls. A decrease in protein kinase affinity to cAMP and an increase in the number of nucleotide binding sites were revealed with a simultaneous decrease in cAMP level. The weakening of hormonal control of cAMP-dependent processes is probably the basic cause of muscular weakness and structural changes in skeletal muscles in thyrotoxic myopathy.
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PMID:Pathogenesis of experimental thyrotoxic myopathy. 300 98

The data obtained in mice with experimental thyrotoxic myopathy included a decrease in the median diameter of the muscle fibers by 17.1 per cent and various focal degenerative changes in less than 20 per cent of the muscle fibers; a statistically significant elevation in the activity of alpha-glycerophosphate dehydrogenase, as well as a reduction in phosphorylase activity and glycogen levels. There was also a significant diminution in the median diameter of the motor terminal plates, a decrease in cholinesterase activity and intensified collateral ramification of the distal axons. The major cause of the muscular weakness and structural changes in the skeletal muscles in thyrotoxic myopathy seems to lie in lowered cAMP concentrations and a weakened cAMP-dependent regulation of protein kinase.
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PMID:[Pathogenesis of experimental thyrotoxic myopathy]. 624 Aug 78

The PKC1 gene of budding yeast encodes a homolog of the alpha, beta, and gamma isoforms of mammalian PKC that is proposed to regulate a MAPK-activation pathway. Mutants in this pathway undergo cell lysis resulting from a deficiency in cell wall construction when they attempt to grow at elevated temperatures. We show that the PKC1-regulated pathway is important for induced thermotolerance and that the MPK1 protein kinase (the MAPK of this pathway) is strongly activated by mild heat shock. This activation is sustained during growth at high temperature and is dependent on the function of pathway components proposed to function upstream of MPK1, including PKC1. Expression of genes under the control of known heat shock-inducible promoter elements (HSEs and STREs) was not compromised in PKC1 pathway mutants, indicating that this pathway mediates a novel aspect of the yeast heat shock response. We propose that the heat-induced signal for pathway activation is generated in response to weakness in the cell wall created during growth under thermal stress, perhaps as a result of increased membrane fluidity. Evidence is presented that the mechanism by which the cell detects this weakness is by measuring stretch of the plasma membrane.
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PMID:The protein kinase C-activated MAP kinase pathway of Saccharomyces cerevisiae mediates a novel aspect of the heat shock response. 762 92

Myotonic dystrophy (DM) is one of the most common inherited neuromuscular diseases in adults with a global incidence of 1 in 20,000 individuals. DM is an autosomal dominant disorder characterized primarily by myotonia and progressive muscle weakness. DM has unique genetic feature of anticipation, that is, increasing disease severity from generation to generation. DM candidate gene encodes a protein kinase (myotonin protein kinase; MtPK) expressed ubiquitously, and nearly all cases of DM displayed expansion (about 100 to 1,000) of the CTG repeat in the 3'-untranslated region, whose repeating number is in proportion to the severity of the condition. The physiological functions, however, of MtPK and the triplet repeat expansion are not yet clear. Thus, to elucidate the molecular mechanism of DM and for therapy of DM at last, we started biochemical analysis of MtPK and molecular biological study of CTG repeat. First of all, we have cloned a full length cDNA for MtPK, which encodes 625 amino acid residues and contains 5 repeats of CTG. Detailed structural analysis of MtPK and expression study of MtPK using the cDNA were performed, and physiological function of MtPK is discussed based on the results.
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PMID:[CTG-repeat in myotonin protein kinase]. 777 20

Unstable expansion of the CTG repeats in the 3' untranslated region encoding a member of the protein kinase family in the q13.3 band on chromosome 19 is a mutation specific for myotonic dystrophy. To examine the correlation between clinical expression and CTG trinucleotide repeat length, we carried out Southern blot analysis in a family with myotonic dystrophy. In this pedigree, the expanded CTG repeats were transmitted maternally. The mother had three female children. The mother had about 200 CTG repeats, and the number of repeats for each child was about 800, 1500 and 1600 in birth order. The mother and the patient with 800 repeats were unaware of muscle weakness or myotonia. Symptoms were present from age 3 years in the patient with 1500 repeats and from birth in the one with 1600 repeats. Although the mother menstruated regularly, the patients with 800 and 1500 repeats both menstruated irregularly, and the one with 1600 repeats has never menstruated. The age of onset and severity of the disease were correlated with the size of the expanded repeats. Endocrinological studies revealed that the basal levels of the gonadotropins, PRL and E2 were within normal range, and a pituitary response to LHRH was observed. These data suggest that the amenorrhea and menstrual irregularities were caused by a suprahypophyseal dysfunction. When expanded CTG repeats are transmitted maternally, abnormal products resulting from the metabolic disturbance in the affected mother may harm the fetus in utero. A heterozygous fetus, who has more CTG repeats, may be unable to metabolize the pathologic products sufficiently and therefore may become more severely affected. This may explain the exclusive maternal transmission of congenital myotonic dystrophy.
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PMID:CTG trinucleotide repeat length and clinical expression in a family with myotonic dystrophy. 873 4

1. Raising the intracellular [Ca2+] for 10 s at 23 degrees C abolished depolarization-induced force responses in mechanically skinned muscle fibres of toad and rat (half-maximal effect at 10 and 23 microM, respectively), without affecting the ability of caffeine or low [Mg2+] to open the ryanodine receptor (RyR)/Ca2+ release channels. Thus, excitation-contraction coupling was lost, even though the Ca2+ release channels were still functional. Coupling could not be restored in the duration of an experiment (up to 1 h). 2. The Ca(2+)-dependent uncoupling had a Q10 > 3.5, and was three times slower at pH 5.8 than at pH 7.1. Sr2+ caused similar uncoupling at twenty times higher concentration, but Mg2+, even at 10 mM, was ineffective. Uncoupling was not noticeably affected by removal of ATP or application of protein kinase or phosphatase inhibitors. 3. Confocal laser scanning microscopy showed that the transverse tubular system was sealed in its entirety in mechanically skinned fibres and that its integrity was maintained in uncoupled fibres. Electron microscopy revealed distorted or severed triad junctions and Z-line aberrations in uncoupled fibres. 4. Only when uncoupling was induced at a relatively slow rate (e.g. over 60 s with 2.5 microM Ca2+) could it be prevented by the protease inhibitor leupeptin (1 mM). Immunostaining of Western blots showed no evidence of proteolysis of the RyR, the alpha 1-subunit of dihydropyridine receptor (DHPR) or triadin in uncoupled fibres. 5. Fibres which, whilst intact, were stimulated repeatedly by potassium depolarization with simultaneous application of 30 mM caffeine showed reduced responsiveness after skinning to depolarization but not to caffeine. Rapid release of endogenous Ca2+, or raised [Ca2+] under conditions which minimized the loss of endogenous diffusible myoplasmic molecules from the skinned fibre, caused complete uncoupling. Taken together, these results suggest that Ca(2+)-dependent uncoupling can also occur in intact fibres. 6. This Ca(2+)-dependent loss of depolarization-induced Ca2+ release may play an important feedback role in muscle by stopping Ca2+ release in localized areas where it is excessive and may be responsible for long-lasting muscle fatigue after severe exercise, as well as contributing to muscle weakness in various dystrophies.
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PMID:Raised intracellular [Ca2+] abolishes excitation-contraction coupling in skeletal muscle fibres of rat and toad. 884 31

The exacerbation of symptoms after exercise differentiates Chronic fatigue syndrome (CFS) from several other fatigue-associated disorders. Research data point to an abnormal response to exercise in patients with CFS compared to healthy sedentary controls, and to an increasing amount of evidence pointing to severe intracellular immune deregulations in CFS patients. This manuscript explores the hypothetical interactions between these two separately reported observations. First, it is explained that the deregulation of the 2-5A synthetase/RNase L pathway may be related to a channelopathy, capable of initiating both intracellular hypomagnesaemia in skeletal muscles and transient hypoglycemia. This might explain muscle weakness and the reduction of maximal oxygen uptake, as typically seen in CFS patients. Second, the activation of the protein kinase R enzyme, a characteristic feature in atleast subsets of CFS patients, might account for the observed excessive nitric oxide (NO) production in patients with CFS. Elevated NO is known to induce vasidilation, which may limit CFS patients to increase blood flow during exercise, and may even cause and enhanced postexercise hypotension. Finally, it is explored how several types of infections, frequently identified in CFS patients, fit into these hypothetical pathophysiological interactions.
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PMID:Chronic fatigue syndrome: intracellular immune deregulations as a possible etiology for abnormal exercise response. 1508 2

Verrucotoxin is the major component of venom from the stonefish (Synanceia verrucosa). Stings from the dorsal spines of the stonefish produce intensive pain, convulsions, hypotension, paralysis, respiratory weakness and collapse of the cardiovascular system, occasionally leading to death. It has been reported that verrucotoxin might modulate ATP-sensitive K+ (KATP) current in frog atrial fibers. However, the mechanism by which verrucotoxin acts on KATP current remains unclear. In this study, we examined whether verrucotoxin inhibited KATP current in guinea pig ventricular myocytes, using the patch clamp method. Verrucotoxin suppressed KATP current induced by pinacidil (KATP channel opener) in a concentration-dependent manner, with a half maximum concentration of 16.3 microg/ml. The effect of verrucotoxin on KATP current was suppressed by atropine (1 microM), a muscarinic receptor antagonist, or by 4-diphenylacetoxy-N-methylpiperidine (100 nM), a muscarinic M3 receptor antagonist. Furthermore, the effect of verrucotoxin on KATP current was attenuated by the protein kinase C (PKC) inhibitor chelerythrine (10 microM) and calphostin C (10 microM), yet not by the cAMP-dependent protein kinase (PKA) inhibitor H-89 (0.5 microM). These results suggest that verrucotoxin inhibits KATP current through the muscarinic M3 receptor-PKC pathway. These findings enhance our understanding of the toxic effects of verrucotoxin from the stonefish.
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PMID:Verrucotoxin inhibits KATP channels in cardiac myocytes through a muscarinic M3 receptor-PKC pathway. 1736 22

Desmin myopathy was identified in a Chinese man with complete heart block and mild proximal and distal limb weakness. A novel heterozygous missense S13F mutation of the desmin gene was found to be associated with the myopathy. Family members carrying the mutation showed a similar or milder phenotype. The mutation is located at a protein kinase-C phosphorylation site within a highly conserved nonapeptide sequence in the head domain of the desmin protein. Expression of the mutant desmin cDNA in cell lines induced large desmin accumulations associated with preservation of a filamentous network.
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PMID:Characterization of a novel S13F desmin mutation associated with desmin myopathy and heart block in a Chinese family. 1806 54


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