Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.31 (AMP-activated protein kinase)
 13,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

AMP-activated protein kinase (AMPK) is expressed in the apical membrane of cortical thick ascending limb, distal, and collecting tubules as well as macula densa cells of the kidneys. AMPK is an active modulator of epithelial Na(+) channels, Na(+)-2Cl(-)-K(+) cotransporter, and the ATP-dependent potassium channel. The present experiments explored whether AMPK participates in the regulation of tubuloglomerular feedback (TGF) and renal tubular sodium handling. To this end, renal clearance and micropuncture experiments were performed in anesthetized rats. Under normal NaCl diet, neither TGF response nor renal fluid and sodium excretion were altered by pharmacological activation of AMPK in vivo. However, under high NaCl diet, the TGF response was significantly enhanced after intravenous or intratubular application of the AMPK activator AICAR. Moreover, AICAR application significantly increased fractional delivery of fluid and sodium to the end of the proximal tubule. High dietary NaCl intake increased the renal transcript levels encoding the AMPK-alpha1 subunit, while it decreased the expression of AMPK-beta1 and AMPK-gamma2 subunits. Immunoblots revealed that high dietary NaCl intake reduced renal expression of activated AMPK by about three times compared to normal NaCl diet whereas additional AICAR application increased AMPK activity. Our results suggest that AMPK regulates tubuloglomerular balance as well as tubular transport upon change of renal work load.
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PMID:In vivo stimulation of AMP-activated protein kinase enhanced tubuloglomerular feedback but reduced tubular sodium transport during high dietary NaCl intake. 2034 93

A wide variety of agents activate AMPK, but in many cases the mechanisms remain unclear. We generated isogenic cell lines stably expressing AMPK complexes containing AMP-sensitive (wild-type, WT) or AMP-insensitive (R531G) gamma2 variants. Mitochondrial poisons such as oligomycin and dinitrophenol only activated AMPK in WT cells, as did AICAR, 2-deoxyglucose, hydrogen peroxide, metformin, phenformin, galegine, troglitazone, phenobarbital, resveratrol, and berberine. Excluding AICAR, all of these also inhibited cellular energy metabolism, shown by increases in ADP:ATP ratio and/or by decreases in cellular oxygen uptake measured using an extracellular flux analyzer. By contrast, A769662, the Ca(2+) ionophore, A23187, osmotic stress, and quercetin activated both variants to varying extents. A23187 and osmotic stress also increased cytoplasmic Ca(2+), and their effects were inhibited by STO609, a CaMKK inhibitor. Our approaches distinguish at least six different mechanisms for AMPK activation and confirm that the widely used antidiabetic drug metformin activates AMPK by inhibiting mitochondrial respiration.
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PMID:Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. 2051 26

Human mutations in the gene PRKAG2 encoding the gamma2 subunit of AMP-activated protein kinase (AMPK) cause a glycogen storage cardiomyopathy. Transgenic mice (TG(T400N)) with the human T400N mutation exhibit inappropriate activation of AMPK and consequent glycogen storage in the heart. Although increased glucose uptake and activation of glycogen synthesis have been documented in PRKAG2 cardiomyopathy, the mechanism of increased glucose uptake has been uncertain. Wildtype (WT), TG(T400N), and TG(alpha2DN) (carrying a dominant negative, kinase dead alpha2 catalytic subunit of AMPK) mice were studied at ages 2-8 weeks. Cardiac mRNA expression of sodium-dependent glucose transporter 1 (SGLT1), but not facilitated-diffusion glucose transporter 1 (GLUT1) or GLUT4, was increased approximately 5- to 7-fold in TG(T400N) mice relative to WT. SGLT1 protein was similarly increased at the cardiac myocyte sarcolemma in TG(T400N) mice. Phlorizin, a specific SGLT1 inhibitor, attenuated cardiac glucose uptake in TG(T400N) mice by approximately 40%, but not in WT mice. Chronic phlorizin treatment reduced cardiac glycogen content by approximately 25% in TG(T400N) mice. AICAR, an AMPK activator, increased cardiac SGLT1 mRNA expression approximately 3-fold in WT mice. Relative to TG(T400N) mice, double transgenic (TG(T400N)/TG(alpha2DN)) mice had decreased ( approximately 50%) cardiac glucose uptake and decreased (approximately 70%) cardiac SGLT1 expression. TG(T400N) hearts had increased binding activity of the transcription factors HNF-1 and Sp1 to the promoter of the gene encoding SGLT1. Our data suggest that upregulation of cardiac SGLT1 is responsible for increased cardiac glucose uptake in the TG(T400N) mouse. Increased AMPK activity leads to upregulation of SGLT1, which in turn mediates increased cardiac glucose uptake.
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PMID:SGLT1, a novel cardiac glucose transporter, mediates increased glucose uptake in PRKAG2 cardiomyopathy. 2060 Jan 2

Enzyme AMPK is a part of the family of serine/threonine specific protein kinases. AMPK plays important role in the transfer extracellular signals through phosphorylation of multiple substrates in different metabolic reactions of skeletal muscles. AMPK is geterotrimetric complex, consisting of the catalytic subunit (AMPKalpha) and two regulatory subunits (AMPKbeta and AMPKgamma), which are encoded by seven different high-homologous genes (alpha1, alpha2, beta1, beta2, gamma1, gamma2, gamma3). AMPK regulates skeletal muscle metabolism through phosphorylation of various enzymes such as carbohydrate, lipid and protein metabolism, as well as factors of transcription and initiation. The AMPK expression occurs in response to a changing metabolic requests muscle cells and it leads to increased energy metabolism. The data of recent studies suggest the important role of AMPK in the regulation of intracellular metabolism and point to the need to study the molecular mechanisms involved in the regulation of gene expression in skeletal muscle.
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PMID:[Participation AMPK in the regulation of skeletal muscles metabolism]. 2445 75

Familial Wolff-Parkinson-White (WPW) syndrome is an autosomal dominant inherited disease and consists of a small percentage of WPW syndrome which exhibits ventricular pre-excitation by development of accessory atrioventricular pathway. A series of mutations in PRKAG2 gene encoding gamma2 subunit of 5'AMP-activated protein kinase (AMPK) has been identified as the cause of familial WPW syndrome. AMPK is one of the most important metabolic regulators of carbohydrates and lipids in many types of tissues including cardiac and skeletal muscles. Patients and animals with the mutation in PRKAG2 gene exhibit aberrant atrioventricular conduction associated with cardiac glycogen overload. Recent studies have revealed "novel" significance of canonical pathways leading to glycogen synthesis and provided us profound insights into molecular mechanism of the regulation of glycogen metabolism by AMPK. This review focuses on the molecular basis of the pathogenesis of cardiac abnormality due to PRKAG2 mutation and will provide current overviews of the mechanism of glycogen regulation by AMPK. J. Med. Invest. 65:1-8, February, 2018.
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PMID:Molecular Pathogenesis of Familial Wolff-Parkinson-White Syndrome. 2959 77


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