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

---

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

We describe four members of the same family with a very similar ECG pattern characterized by conduction defects (right bundle branch block, frequent left anterior hemiblock, atrial hypertrophy, and sometimes severe nodal dysfunction) contrasting with a short PR interval. Significant clinical events were reported only after 60 years of age. A mutation in the gamma2 subunit of the AMP activated protein kinase gene (PRKAG2) was identified in the four members of the family, with an autosomal dominant inheritance. The phenotype observed in this family appears different from that previously described as associated with this gene as neither left ventricular hypertrophy nor Wolff-Parkinson-White syndrome was present. These findings extend the phenotype associated with the PRKAG2 gene and emphasize an additional cause of familial conduction defect.
...
PMID:A familial form of conduction defect related to a mutation in the PRKAG2 gene. 1748 51

The Tottering (cacna1a(tg)) mouse arose as a consequence of a spontaneous mutation in cacna1a, the gene encoding the pore-forming subunit of the pre-synaptic P/Q-type voltage-gated calcium channel (VGCC, Ca(V)2.1). The mouse phenotype includes ataxia and intermittent myoclonic seizures which have been attributed to impaired excitatory neurotransmission at cerebellar granule cell (CGC) parallel fiber-Purkinje cell (PF-PC) synapses [Zhou YD, Turner TJ, Dunlap K (2003) Enhanced G-protein-dependent modulation of excitatory synaptic transmission in the cerebellum of the Ca(2+)-channel mutant mouse, tottering. J Physiol 547:497-507]. We hypothesized that the expression of cerebellar GABA(A) receptors may be affected by the mutation. Indeed, abnormal GABA(A) receptor function and expression in the cacna1a(tg) forebrain has been reported previously [Tehrani MH, Barnes EM Jr (1995) Reduced function of gamma-aminobutyric acid A receptors in tottering mouse brain: role of cAMP-dependent protein kinase. Epilepsy Res 22:13-21; Tehrani MH, Baumgartner BJ, Liu SC, Barnes EM Jr (1997) Aberrant expression of GABA(A) receptor subunits in the tottering mouse: an animal model for absence seizures. Epilepsy Res 28:213-223]. Here we show a deficit of 40.2+/-3.6% in the total number of cerebellar GABA(A) receptors expressed (gamma2+delta subtypes) in adult cacna1a(tg) relative to controls. [(3)H]Muscimol autoradiography identified that this was partly due to a significant loss of CGC-specific alpha6 subunit-containing GABA(A) receptor subtypes. A large proportion of this loss of alpha6 receptors was attributable to a significantly reduced expression of the CGC-specific benzodiazepine-insensitive Ro15-4513 (BZ-IS) binding subtype, alpha6betagamma2 subunit-containing receptors. BZ-IS binding was reduced by 36.6+/-2.6% relative to controls in cerebellar membrane homogenates and by 37.2+/-3.7% in cerebellar sections. Quantitative immunoblotting revealed that the steady-state expression level of alpha6 and gamma2 subunits was selectively reduced relative to controls by 30.2+/-8.2% and 38.8+/-13.1%, respectively, alpha1, beta3 and delta were unaffected. Immunohistochemically probed control and cacna1a(tg) cerebellar sections verified that alpha6 and gamma2 subunit expression was reduced and that this deficit was restricted to the CGC layer. Thus, we have shown that abnormal cerebellar P/Q-type VGCC activity results in a deficit of CGC-specific subtype(s) of GABA(A) receptors which may contribute to, or may be a consequence of the impaired cerebellar network signaling that occurs in cacna1a(tg) mice.
...
PMID:Aberrant cerebellar granule cell-specific GABAA receptor expression in the epileptic and ataxic mouse mutant, Tottering. 1761 9

Mutation in PRKAG2 encoding the gamma2 subunit of the AMP activated protein kinase (AMPK) cause human cardiomyopathy characterized by hypertrophy, Wolff-Parkinson-White syndrome, conduction system disease and glycogen storage in the myocardium. AMPK is a master metabolic regulator activated by hormones and energy deficient states. A heterotrimer enzyme comprising the catalytic alpha- and regulatory beta-and gamma-subunits was preserved through evolution and is ubiquitously expressed among mammalian tissues. AMPK is activated by AMP and inhibited by ATP that competes for binding to the regulatory sites on the gamma-subunit. Upstream kinases which phosphorylate Thr172 on the catalytic subunit activate the enzyme during exercise, ischemia, in response to sympathetic stimulation and hormones such as leptin and adiponectin. AMPK operates by phosphorylating its target proteins such as Acetyl CoA Carboxylase. Its classic functions include decreased fat synthesis in liver and adipose tissues, increased fatty acid oxidation, stimulating muscle glucose uptake and glycolysis. Altogether, these activities serve to restore the cellular and whole body energy balance. Human mutations which disrupt the nucleotide-binding affinity of the gamma2 subunit lead to loss of inhibition by ATP and inappropriate activate AMPK under resting conditions. As a result, myocytes recruit energy metabolites in excess of demand, causing storage of glycogen. Will AMPK ever emerge as a therapeutic target? Bench experiments suggest its potential in treating diabetes, ischemia and cell cycle regulation but much work is needed until these developments reach the bedside.
...
PMID:[AMP-activated protein kinase: how a mistake in energy gauge causes glycogen storage]. 1799 Mar 92

Conduction defects are usually secondary to elective aging of the conduction pathways. However, some familial and genetic forms are now being described. Here we report a particular electrocardiographic pattern in four members of the same family over three generations, naturally leading to the suspicion of a hereditary origin. The ECG appearance is very specific and includes conduction defects (RBBB and occasionally left anterior hemiblock), short PR interval, pseudo appearance of atrial hypertrophy, and occasionally sinus dysfunction or supraventricular extrasystole. Gene analysis identified a R302Q mutation of the gamma2 subunit producing AMP protein kinase, coded by the gene PRKAG2. This is a wrong sense mutation present in the heterozygous state in each of those displaying the ECG anomalies, and is transmitted in an autosomal dominant fashion. The clinical picture here appears to constitute a clinical entity distinct from those previously described as being associated with mutations of the PRKAG2 gene, without any left ventricular hypertrophy or Wolff-Parkinson-White syndrome.
...
PMID:[A familial form of conduction defects associated with a PRKAG2 gene mutation]. 1803 3

The present study was aimed at evaluating the molecular mechanisms associated with the differences in muscle glycogen content and breast meat quality between 2 experimental lines of chicken divergently selected on abdominal fatness. The glycogen at death (estimated through the glycolytic potential) of the pectoralis major muscle and the quality of the resulting meat were estimated in the 2 lines. The fat chickens exhibited greater glycolytic potential, and in turn lower ultimate pH than the lean chickens. Consequently, the breast meat of fat birds was paler and less colored (i.e., less red and yellow), and exhibited greater drip loss compared with that of lean birds. In relation to these variations, transcription and activation levels of adenosine monophosphate-activated protein kinase (AMPK) were investigated. The main difference observed between lines was a 3-fold greater level of AMPK activation, evaluated through phosphorylation of AMPKalpha-(Thr(172)), in the muscle of lean birds. At the transcriptional level, data indicated concomitant down- and upregulation for the gamma1 and gamma2 AMPK subunit isoforms, respectively, in the muscle of lean chickens. Transcriptional levels of enzymes directly involved in glycogen turnover were also investigated. Data showed greater gene expression for glycogen synthase, glycogen phosphorylase, and the gamma subunit of phosphorylase kinase in lean birds. Together, these data indicate that selection on body fatness in chicken alters the muscle glycogen turnover and content and consequently the quality traits of the resulting meat. Alterations of AMPK activity could play a key role in these changes.
...
PMID:Adenosine monophosphate-activated protein kinase involved in variations of muscle glycogen and breast meat quality between lean and fat chickens. 1859 65

Intracellullar trafficking of lipids is fundamental to membrane biogenesis. For the synthesis of sphingomyelin, ceramide is transported from the endoplasmic reticulum to the Golgi apparatus by the ceramide transfer protein CERT. CERT is phosphorylated by protein kinase D at S132 and subsequently multiple times in a serine-repeat motif, resulting in its inactivation. However, the kinase involved in the multiple phosphorylation remains unclear. Here, we identify the gamma2 isoform of casein kinase I (CKIgamma2) as a kinase whose overexpression confers sphingomyelin-directed toxin-resistance to Chinese hamster ovary cells. In a transformant stably expressing CKIgamma2, CERT was hyperphosphorylated, and the intracellular trafficking of ceramide was retarded, thereby reducing de novo sphingomyelin synthesis. The reduction in the synthesis of sphingomyelin caused by CKIgamma2 was reversed by the expression of CERT mutants that are not hyperphosphorylated. Furthermore, CKIgamma2 directly phosphorylated CERT in vitro. Among three gamma isoforms, only knockdown of gamma2 isoform caused drastic changes in the ratio of hypo- to hyperphosphorylated form of CERT in HeLa cells. These results indicate that CKIgamma2 hyperphosphorylates the serine-repeat motif of CERT, thereby inactivating CERT and down-regulating the synthesis of sphingomyelin.
...
PMID:Casein kinase I{gamma}2 down-regulates trafficking of ceramide in the synthesis of sphingomyelin. 1900 13

Protein serine/threonine phosphorylation in mammalian sperm flagella has been considered to play important roles in regulation of motility. Protein phosphorylation state reflects balance of enzymatic activities between protein phosphatases and protein kinases [predominantly protein kinase A (PKA)]. The aims of this study were to disclose roles of protein phosphatases in the regulation of sperm motility and to provide evidence for suppression of PKA full activation by protein phosphatases in sperm flagella. Mouse epididymal spermatozoa were incubated with a cell-permeable protein phosphatase 1 (PP1)/protein phosphatase 2A (PP2A) inhibitor (calyculin A: 25-125 nM) at 37.5 C. After incubation, they were used for immunodetection of phosphorylated proteins, PKA and PP1 gamma2, assessment for motility and co-immunoprecipitation of PP1gamma2 with PKA. Incubation with calyculin A enhanced the phosphorylation states of several proteins (>250 kDa, 170 kDa, 155 kDa, 140 kDa and 42 kDa for serine/threonine phosphorylation and 70 kDa for tyrosine phosphorylation) and PKA catalytic subunits [at the autophosphorylation residue (Thr-197) for its full enzymatic activation] in the flagella. Coincidently, this incubation induced changes of sperm flagellar movement from the progressive type to the hyperactivation-like type. Indirect immunofluorescence and co-immunoprecipitation showed that PKA was co-localized with PP1 gamma2 in the principal pieces of sperm flagella. These findings suggest that calyculin A-sensitive protein phosphatases (PP1/PP2A) suppress full activation of PKA as well as enhancement of the phosphorylation states of other flagellar proteins in sperm flagella in order to prevent precocious changes of flagellar movement from the progressive type to hyperactivation.
...
PMID:Calyculin A-sensitive protein phosphatases are involved in maintenance of progressive movement in mouse spermatozoa in vitro by suppression of autophosphorylation of protein kinase A. 1929 61

Human mutations in PRKAG2, the gene encoding the gamma2 subunit of AMP activated protein kinase (AMPK), cause a glycogen storage cardiomyopathy. In a transgenic mouse with cardiac specific expression of the Thr400Asn mutation in PRKAG2 (TG(T400N)), we previously reported initial cardiac hypertrophy (ages 2-8 weeks) followed by dilation and failure (ages 12-20 weeks). We sought to elucidate the molecular mechanisms of cardiac hypertrophy. TG(T400N) mice showed significantly increased cardiac mass/body mass ratios up to approximately 3-fold beginning at age 2 weeks. Cardiac expression of ANP and BNP were approximately 2- and approximately 5-fold higher, respectively, in TG(T400N) relative to wildtype (WT) mice at age 2 weeks. NF-kappaB activity and nuclear translocation of the p50 subunit were increased approximately 2- to 3-fold in TG(T400N) hearts relative to WT during the hypertrophic phase. Phosphorylated Akt and p70S6K were elevated approximately 2-fold as early as age 2 weeks. To ascertain whether these changes in TG(T400N) mice were a consequence of increased AMPK activity, we crossbred TG(T400N) with TG(alpha2DN) mice, which express a dominant negative, kinase dead mutant of the AMPK alpha2 catalytic subunit and have low myocardial AMPK activity. Genetic reversal of AMPK overactivity led to a reduction in hypertrophy, nuclear translocation of NF-kappaB, phosphorylated Akt, and p70S6K. We conclude that inappropriate activation of AMPK secondary to the T400N PRKAG2 mutation is associated with the early activation of NF-kappaB and Akt signaling pathway, which mediates cardiac hypertrophy.
...
PMID:Activation of cardiac hypertrophic signaling pathways in a transgenic mouse with the human PRKAG2 Thr400Asn mutation. 2000 92

The stimulation of glucose uptake into peripheral tissues is an important mechanism for the removal of glucose in blood and for the management of diabetes mellitus (DM). Since recent results have demonstrated the beneficial effects of flavonoids in relation to DM, this study was designed to examine the effects of 7-O-methylaromadendrin (7-O-MA), a flavonoid isolated from Inula viscosa, on glucose uptake into liver and fat tissue, and investigate the molecular mechanisms involved. 7-O-MA at 10 microM significantly stimulated insulin-induced glucose uptake measured by 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose (2-NBDG) in both human hepatocellular liver carcinoma (HepG2) cells and differentiated 3T3-L1 adipocytes. Adipocyte-specific fatty acid binding protein (aP2) gene expression was increased by 7-O-MA in adipocytes, and both gene and protein level of peroxisome proliferator-activated receptor gamma2 (PPARgamma2) was also increased. Moreover, 7-O-MA stimulated the reactivation of insulin-mediated phosphorylation of phosphatidylinositol 3-kinase (PI3K)-linked protein kinase B (Akt/PKB) and adenosine 5'-monophosphate-activated protein kinase (AMPK) in high glucose-induced, insulin-resistant HepG2 cells, and this effect was blocked by either LY294002, a PI3K inhibitor, or compound C, an AMPK inhibitor. Therefore, these results suggest that 7-O-MA might stimulate glucose uptake via PPARgamma2 activation and improve insulin resistance via PI3K and AMPK-dependent pathways, and be a potential candidate for the management of type 2 DM.
...
PMID:7-O-methylaromadendrin stimulates glucose uptake and improves insulin resistance in vitro. 2082 63

Many studies have been devoted to the identification of genes involved in experience-dependent plasticity in the visual cortex. To discover new candidate genes, we have reexamined data from one such study on ocular dominance (OD) plasticity in recombinant inbred BXD mouse strains. We have correlated the level of plasticity with the gene expression data in the neocortex that have become available for these same strains. We propose that genes with a high correlation are likely to play a role in OD plasticity. We have tested this hypothesis for genes whose inactivation is known to affect OD plasticity. The expression levels of these genes indeed correlated with OD plasticity if their levels showed strong differences between the BXD strains. To narrow down our candidate list of correlated genes, we have selected only those genes that were previously found to be regulated by visual experience and associated with pathways implicated in OD plasticity. This resulted in a list of 32 candidate genes. The list contained unproven, but not unexpected candidates such as the genes for IGF-1, NCAM1, NOGO-A, the gamma2 subunit of the GABA(A) receptor, acetylcholine esterase, and the catalytic subunit of cAMP-dependent protein kinase A. This demonstrates the viability of our approach. More interestingly, the following novel candidate genes were identified: Akap7, Akt1, Camk2d, Cckbr, Cd44, Crim1, Ctdsp2, Dnajc5, Gnai1, Itpka, Mapk8, Nbea, Nfatc3, Nlk, Npy5r, Phf21a, Phip, Ppm1l, Ppp1r1b, Rbbp4, Slc1a3, Slit2, Socs2, Spock3, St8sia1, Zfp207. Whether all these novel candidates indeed function in OD plasticity remains to be established, but possible roles of some of them are discussed in the article.
...
PMID:Candidate genes in ocular dominance plasticity. 2234 57


<< Previous 1 2 3 4

---