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 autosomal dominant neuromuscular disease. The mutation has been identified as an unstable trinucleotide CTG repeat in a sequence encoding a putative cAMP-dependent protein kinase. The CTG repeat varies in length between affected siblings, and generally increases through generations in parallel with increasing severity of the disease. Congenital myotonic dystrophy, which represents the most severe phenotype, is exclusively maternally inherited. In this report, we show, by Northern blot analysis, that no mutated enlarged transcript is detectable in a 20-week-old DM fetus and in two congenitally affected infants. Furthermore, in skeletal and cardiac muscle of the DM fetus, we observed by RNA analysis, including Northern blot and RT-PCR, an unexpectedly low expression of the paternal wild type allele. Varying degrees of expression of the mutant and/or the normal allele might therefore account for the characteristic features of the congenital form and the extreme variability of the disease.
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PMID:Myotonic dystrophy: absence of CTG enlarged transcript in congenital forms, and low expression of the normal allele. 769 46

Cardiac troponin (Tn) I (CTnI), compared with skeletal TnI, contains extra amino acids (32 to 33) at its amino terminus, including two adjacent serine residues. These two serine residues are believed to be phosphorylated by protein kinase A (PKA) upon stimulation of the heart by beta-agonists. In this study, we found that phosphorylation of a cardiac skinned muscle preparation by PKA, mainly at CTnI, results in a decrease in the Ca2+ sensitivity of muscle contraction. The pCa50 decreased by approximately 0.27 +/- 0.06 pCa units upon phosphorylation. To study cardiac muscle relaxation, we used diazo-2, a photolabile Ca2+ chelator with a low Ca2+ affinity in its intact form that is converted to a high-affinity form after photolysis. We found that the rate of cardiac muscle relaxation increased from a time of half-relaxation (t1/2) = 110 +/- 10 milliseconds to t1/2 = 70 +/- 8 milliseconds after CTnI phosphorylation. This result demonstrates that CTnI phosphorylation can be linked with the increased rate of muscle relaxation in a relatively intact muscle preparation. Since CTnI phosphorylation has been shown previously to affect the Ca2+ affinity and Ca2+ off-rate of CTnC in vitro, it is likely that the faster relaxation seen here reflects faster dissociation of Ca2+ from cardiac TnC (CTnC). Model calculations show that increased dissociation of Ca2+ from CTnC, coupled with the faster uptake of Ca2+ by the sarcoplasmic reticulum stimulated by PKA phosphorylation of phospholamban, can account for the faster relaxation seen in the inotropic response of the heart to catecholamines.
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PMID:Cardiac troponin I phosphorylation increases the rate of cardiac muscle relaxation. 775 57

Vascular tone is regulated by a variety of neurotransmitters, vasoactive hormones and autacoids, and vasoactive drugs. These actions are mediated, at least in part, by actions on the membrane ion channels, exerted either directly or indirectly. In this article, we described evidence that four different protein kinase systems (PK-A, PK-G, PK-C, and Ca2+/CaM-PK) act on and modulate the L-type Ca2+ slow channels in VSM cells and other types of cells. In cardiac muscle, both cAMP/PK-A and cGMP/PK-G have opposing effects. cAMP/PK-A stimulating and cGMP/PK-G inhibiting. In VSM, both cyclic nucleotides and their related kinases act in the same direction, namely both inhibit ICa(L). In skeletal muscle, both cAMP and cGMP also act in the same direction on ICa(L), but to stimulate. Ca2+ channel phosphorylation may be an important mechanism for the cyclic nucleotide-dependent actions of some vasodilators. In cardiac muscle, in addition to the slower indirect pathway--exerted via cAMP/PK-A--there is a faster more-direct pathway for ICa(L) stimulation by the beta-adrenergic receptor. This latter pathway involves direct modulation of the channel activity by the alpha subunit of the Gs-protein (Gs alpha). The two pathways (direct and indirect) are also present in VSM cells, although the indirect pathway produces inhibition of ICa(L)). PK-C and calmodulin-PK also may play roles in regulation of the L-type Ca2+ channels in smooth muscle cells, possibly mediated by phosphorylation of some regulatory-type of protein. Thus, it appears that the L-type Ca2+ slow channel is a complex structure, including perhaps several associated regulatory proteins, which can be regulated by a number of factors intrinsic and extrinsic to the cell (Figs 9, 14).
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PMID:Regulation of L-type calcium channels of vascular smooth muscle cells. 776 Mar 90

The secosteroid hormone 1,25(OH)2-vitamin D3 rapidly activates voltage-dependent Ca2+ channels of the L-type in skeletal and cardiac muscle cells by a non-genomic mechanism which involves guanine nucleotide binding (G) protein-medicated stimulation of the adenylate cyclase/cAMP/protein kinase A messenger system. Modifications in calmodulin intracellular distribution induced by PKA-dependent membrane protein phosphorylation may participate in the fast regulation of muscle Ca2+ influx by 1,25(OH)2D3. The protein kinase C pathway also plays a role modulating 1,25(OH)2D3 signal transduction in muscle by cross-talk with the PKA system. The hormone sequentially activates phospholipases C and D providing diacylglycerol for PKC activation and inositol triphosphate for intracellular Ca2+ mobilization. In addition, 1,25(OH)2D3 rapidly stimulates phospholipase A2 generating arachidonic acid for the eicosanoid pathway. Specificity of hormone effects suggests that binding to a muscle membrane-bound receptor mediates these events.
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PMID:Non-genomic signal transduction pathway of vitamin D in muscle. 788 98

The interaction of troponin I (CTnI) with troponin C (CTnC) from bovine cardiac muscle was studied using CTnC modified at Cys35 and Cys84 with the fluorescent probe 2-[(4'-iodoacetamido)-anilino]naphthalene-6-sulfonic acid (CTnCIAANS). The association constant for complex formation between the two proteins was determined at 20 degrees C in 0.4 M KCl, 1 mM DTT, 1 mM EGTA, and 25 mM MOPS, pH 7.2. In the presence of EGTA, Mg2+, and Ca2+ these constants were 1.46 x 10(7), 4.1 x 10(7), and 12.7 x 10(7) M-1, respectively, with corresponding free energy values of -9.62, -10.23, and -10.88 kcal mol-1. The CTnI-CTnCIAANS complex was stabilized by -0.61 kcal when the two Ca/Mg sites of CTnCIAANS were saturated with Mg2+ and by -1.26 kcal when all three Ca2+ sites were occupied by Ca2+. These results suggest that calcium activation in cardiac muscle may be accompanied by a coupling free energy of -0.65 kcal. This value is a factor of 4 smaller than the value previously determined, using a similar method, for the (troponin I).(troponin C) complex from skeletal muscle [Wang, C.-K., & Cheung, H.C. (1985) Biophys. J.48, 727-739]. Since CTnC has only one Ca(2+)-specific site and troponin C from skeletal muscle has two such sites, the present result is a factor of 2 smaller than that for the skeletal complex on the basis of a single specific site. Phosphorylation of CTnI by 3',5'-cyclic AMP-dependent protein kinase resulted in a decrease of the association constants by a factor of 2.5-3.5.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Coupling of calcium to the interaction of troponin I with troponin C from cardiac muscle. 791 99

Monoclonal antibodies were used to identify and characterize a novel 90 kDa protein that was specifically localized to the junctional sarcoplasmic reticulum of rabbit skeletal muscle. Biochemical experiments show that the 90 kDa protein is an integral membrane protein of the junctional face membrane and is a substrate for the intrinsic protein kinase in triads. Immunofluorescence staining of serial transverse sections of skeletal muscle with a monoclonal antibody to the 90 kDa protein showed preferential staining of type II "fast" fibers. Specific labeling was confined to the interphase between the A- and I-bands, where the triad structure is localized. Immunoelectron microscopical labeling further indicates that the 90 kDa protein, like the ryanodine receptor/Ca(2+)-release channel and triadin, is confined to the terminal cisternae of the sarcoplasmic reticulum. Western blot analysis with a combination of monoclonal antibodies against the 90 kDa protein shows that it is specifically expressed in skeletal muscle but not in cardiac muscle or brain. Similarly, specific immunofluorescence labeling to the 90 kDa protein was not detected in ventricular myocytes or vascular smooth muscle cells. The junctional localization and phosphorylation of this protein suggest that it may play an important regulatory or structural role in the skeletal muscle triad junction.
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PMID:Characterization and ultrastructural localization of a novel 90-kDa protein unique to skeletal muscle junctional sarcoplasmic reticulum. 796 75

Around the time of birth, cardiac muscle cells lose the capacity to divide and, from this time on, growth of the heart occurs by hypertrophy where each cells gets bigger. The hypertrophic response is characterized by changes in gene expression including expression of the atrial natriuretic factor (ANF) and myosin light chain-2 (MLC-2) genes. In cultured neonatal ventricular myocytes, hypertrophy also involves reorganization of contractile proteins into sarcomeric units. We have investigated the role of the Raf-1 kinase in this response. Activation of an estradiol-regulated Raf-1 protein kinase led to activation of mitogen-activated protein (MAP) kinase and activated expression from the ANF and MLC-2 promoters. Raf-1-induced activation of these genes was inhibited by a kinase deficient mutant of the 44-kDa MAP kinase, Erk1 indicating a requirement for MAP kinases in the Raf-1-induced response. However, activation of Raf-1 was not sufficient to induce the organization of actin into sarcomeric units. Transfection of dominant negative Raf-1 inhibited phenylephrine-induced activation of the ANF and MLC-2 promoters. Transactivation was rescued by the introduction of increased amounts of c-Raf suggesting a role for Raf-1 in the response to alpha-adrenergic agonists. These results suggest that activation of Raf-1 kinase is a critical component of the signal transduction pathway leading to changes in gene expression associated with hypertrophy but that Raf-1 is not sufficient for the regulation of actin organization during the hypertrophic response.
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PMID:Raf-1 kinase activity is necessary and sufficient for gene expression changes but not sufficient for cellular morphology changes associated with cardiac myocyte hypertrophy. 798 77

The clinical manifestation of myotonic dystrophy (DM) is correlated to the extent of expansion of an unstable [CTG]n DNA motif. Recent studies have demonstrated that this trinucleotide motif forms part of the last, 3' untranslated exon of a gene which potentially encodes multiple protein isoforms of a serine/threonine protein kinase (myotonic dystrophy protein kinase, DM-PK). We report here on the development of antisera against synthetic DM-PK peptide antigens and their use in biochemical and histochemical studies. Immunoreactive DM-kinase protein of 53 kD is present at low levels in skeletal and cardiac muscle extracts of DM patients and normal controls. Immunohistochemical staining revealed that DM-PK is localised prominently at sites of neuromuscular and myotendinous junctions (NMJs and MTJs) of human and rodent skeletal muscles. Furthermore, very low levels of immunoreactive DM-PK protein are present in the sarcoplasm of predominantly type I fibres in various muscles. Strikingly, presence of the protein can also be demonstrated for NMJs of muscular tissues of adult and congenital cases of DM, with no gross changes in structural organisation. Our findings provide a basis for further characterisation of the role of the kinase in protein assembly processes or signal mediation at synaptic sites and ultimately for the understanding of the complex pathophysiology of DM.
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PMID:Myotonic dystrophy kinase is a component of neuromuscular junctions. 828 Nov 52

Peptide-chain initiation is inhibited in fast-twitch skeletal muscle, but not heart, of diabetic rats. We have investigated mechanisms that might maintain eukaryotic initiation factor (eIF)-2B activity, preventing loss of efficiency of protein synthesis in heart of diabetic rats but not in fast-twitch skeletal muscle. There was no change in the amount or phosphorylation state of eIF-2 in skeletal or cardiac muscle during diabetes. In contrast, eIF-2B activity was decreased in fast-twitch but not slow-twitch muscle from diabetic animals. NADP+ inhibited partially purified eIF-2B in vitro, but addition of equimolar NADPH reversed the inhibition. The NADPH-to-NADP+ ratio was unchanged in fast-twitch muscle after induction of diabetes but was increased in heart of diabetic rats, suggesting that NADPH also prevents inhibition of eIF-2B in vivo. The activity of casein kinase II, which can phosphorylate and activate eIF-2B in vitro, was significantly lower in extracts of fast-twitch, but not cardiac muscle, of diabetic rats compared with controls. The results presented here demonstrate that changes in eIF-2 alpha phosphorylation are not responsible for the effect of diabetes on eIF-2B activity in fast-twitch skeletal muscle. Modulation of casein kinase II activity may be a factor in the regulation of protein synthesis in muscle during acute diabetes. The activity of eIF-2B in heart might be maintained by the increased NADPH/NADP+.
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PMID:Regulation of eukaryotic initiation factor-2B activity in muscle of diabetic rats. 843 Jul 78

Porcine skeletal and cardiac muscle sarcoplasmic reticulum (SR) vesicle fractions enriched in the ryanodine receptor were phosphorylated in the presence of [gamma-32P]MgATP and either exogenous cAMP-dependent protein kinase (cAMP-PK), or Ca2+ plus calmodulin. Phosphorylation of the cardiac muscle ryanodine receptor in the presence of either cAMP-PK or calmodulin (6.4 and 10.6 pmol Pi/mg SR respectively) was approximately equal to or twice the [3H]ryanodine binding activity of this preparation (5.2 pmol/mg). Furthermore, cardiac muscle ryanodine receptor Pi incorporation catalyzed by cAMP-PK and calmodulin was approximately additive. In skeletal muscle SR, however, the level of cAMP-PK or calmodulin catalyzed phosphorylation of the intact ryanodine receptor (0.2 or 2.9 pmol Pi/mg SR, respectively) was much less than the [3H]ryanodine binding activity of this fraction (11.6 pmol/mg). Furthermore, Pi incorporation into the intact skeletal muscle ryanodine receptor was 3-8-fold less than that incorporated into a component of slightly lower M(r). Although this latter component comigrated with an immunoreactive fragment of the ryanodine receptor on polyacrylamide gels, it did not appear to be derived from the ryanodine receptor. We conclude that the significant phosphorylation of the cardiac muscle SR ryanodine receptor indicates a likely physiological role for protein kinase-mediated regulation of this Ca(2+)-channel. In contrast, the minimal phosphorylation of the skeletal muscle SR ryanodine receptor indicates that such a role of protein kinases is unlikely in this tissue.
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PMID:Phosphorylation of the porcine skeletal and cardiac muscle sarcoplasmic reticulum ryanodine receptor. 843 48


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