Molecular Cloning, Genomic Organization, and Mapping of PRKAG2, a Heart Abundant γ2 Subunit of 5′-AMP-Activated Protein Kinase, to Human Chromosome 7q36

Lang, Tieming; Liu, Yu; Tu, Qiang; Jiang, Jianming; Chen, Zheng; Xin, Yurong; Liu, Guoyang; Zhao, Shouyuan

doi:10.1006/geno.2000.6376

Cited by 57 publications

(42 citation statements)

References 12 publications

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“…The full-length and truncated transcripts, denoted PRKAG2a and PRKAG2b, respectively, are highly expressed in cardiac tissue. 6,7 The previously and currently described mutations are present in exons 7 and 15, and are therefore common to both PRKAG2 transcription products.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it was determined that a smaller transcription product of PRKAG2 exists as a result of an alternative transcription initiation site in intron 4. 6 Thus, this smaller transcript corresponds to exons 5 to 12 of the full-length transcription product. The full-length and truncated transcripts, denoted PRKAG2a and PRKAG2b, respectively, are highly expressed in cardiac tissue.…”

Section: Discussionmentioning

confidence: 99%

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Novel PRKAG2 Mutation Responsible for the Genetic Syndrome of Ventricular Preexcitation and Conduction System Disease With Childhood Onset and Absence of Cardiac Hypertrophy

et al. 2001

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Background-We recently reported a mutation in the PRKAG2 gene to be responsible for a familial syndrome of ventricular preexcitation, atrial fibrillation, conduction defects, and cardiac hypertrophy. We now report a novel mutation in PRKAG2 causing Wolff-Parkinson-White syndrome and conduction system disease with onset in childhood and the absence of cardiac hypertrophy. Methods and Results-DNA was extracted from white blood cells obtained from family members. PRKAG2 exons were amplified by polymerase chain reaction and were screened for mutations by direct sequencing. The genomic organization of the PRKAG2 gene was determined using inter-exon long-range polymerase chain reaction for cDNA sequence not available in the genome database. A missense mutation, Arg531Gly, was identified in all affected individuals but was absent in 150 unrelated individuals. The PRKAG2 gene was determined to consist of 16 exons and is at least 280 kb in size. Conclusions-We identified a novel mutation (Arg531Gly) in the ␥-2 regulatory subunit (PRKAG2) of AMP-activated protein kinase (AMPK) to be responsible for a syndrome associated with ventricular preexcitation and early onset of atrial fibrillation and conduction disease. These observations confirm an important functional role of AMPK in the regulation of ion channels specific to cardiac tissue. The identification of the cardiac ion channel(s) serving as substrate for AMPK not only would provide insight into the molecular basis of atrial fibrillation and heart block but also may suggest targets for the development of more specific therapy for these common rhythm disturbances. he Wolff-Parkinson-White (WPW) syndrome is characterized by electrocardiographic evidence of ventricular preexcitation, which predisposes to supraventricular arrhythmias. 1 Tachycardias mediated by accessory atrioventricular connections, the anatomic substrate for WPW, are the most common tachycardias in children Ͻ12 years of age. 2 WPW as a cause of sudden cardiac death (SCD), presumably as a result of rapidly conducting atrial fibrillation, is well recognized. 3 The prevalence of WPW as a cause of SCD remains unknown because histological evidence is seldom sought at autopsy. However, a recent study of SCD victims Ͻ35 years of age for whom ECGs were available identified WPW in 10.5% of cases. 4 Atrioventricular connections were confirmed by histological examination. 4 We recently identified 5 2 families with familial ventricular preexcitation associated with a high incidence of atrial fibrillation, conduction defects, and cardiac hypertrophy, and we established the responsible genetic defect to be a mutation in the gene that encodes the ␥-2 regulatory subunit (PRKAG2) of AMP-activated protein kinase (AMPK). Paroxysmal atrial fibrillation was particularly frequent, and chronic atrial fibrillation was present in 80% of patients Ͼ50 years of age. See p 3014We now report a third, unrelated family, which also has ventricular preexcitation, atrial fibrillation, and conduction defects. The third family has more seve...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Novel PRKAG2 Mutation Responsible for the Genetic Syndrome of Ventricular Preexcitation and Conduction System Disease With Childhood Onset and Absence of Cardiac Hypertrophy

et al. 2001

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“…Both of the ␥ 2a transcripts encode a protein of 569 amino acids that contains an additional 241 amino acids at its NH 2 -terminus that are not present in the other ␥-subunit genes. The ␥ 2b transcript is 2.4 kb in length and encodes a protein of 328 amino acids that is expressed in the heart, testis, and placenta (75). The ␥ 3 -subunit is expressed exclusively in skeletal muscle (25,144).…”

Section: Structure Of Mammalian Ampkmentioning

confidence: 99%

Role of AMP-activated protein kinase in healthy and diseased hearts

Dolinsky¹,

Dyck²

2006

American Journal of Physiology-Heart and Circulatory Physiology

118

105

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Dolinsky, Vernon W., and Jason R. B. Dyck. Role of AMP-activated protein kinase in healthy and diseased hearts. Am J Physiol Heart Circ Physiol 291: H2557-H2569, 2006. First published July 14, 2006 doi:10.1152/ajpheart.00329.2006.-The heart is capable of utilizing a variety of substrates to produce the necessary ATP for cardiac function. AMP-activated protein kinase (AMPK) has emerged as a key regulator of cellular energy homeostasis and coordinates multiple catabolic and anabolic pathways in the heart. During times of acute metabolic stresses, cardiac AMPK activation seems to be primarily involved in increasing energy-generating pathways to maintain or restore intracellular ATP levels. In acute situations such as mild ischemia or short durations of severe ischemia, activation of cardiac AMPK appears to be necessary for cardiac myocyte function and survival by stimulating ATP generation via increased glycolysis and accelerated fatty acid oxidation. Whereas AMPK activation may be essential for adaptation of cardiac energy metabolism to acute and/or minor metabolic stresses, it is unknown whether AMPK activation becomes maladaptive in certain chronic disease states and/or extreme energetic stresses. However, alterations in cardiac AMPK activity are associated with a number of cardiovascular-related diseases such as pathological cardiac hypertrophy, myocardial ischemia, glycogen storage cardiomyopathy, and Wolff-Parkinson-White syndrome, suggesting the possibility of a maladaptive role. Although the precise role AMPK plays in the diseased heart is still in question, it is clear that AMPK is a major regulator of cardiac energy metabolism. The consequences of alterations in AMPK activity and subsequent cardiac energy metabolism in the healthy and the diseased heart will be discussed. ischemia; cardiac hypertrophy; cardiac energy metabolism; glycogen THE HEART is capable of utilizing a variety of substrates to meet its immense demand for energy. Under normal physiological circumstances, cardiac function is dependent on the production of intracellular ATP derived primarily by the utilization of fatty acids, glucose, and lactate (123). A variety of transport proteins and regulatory enzymes control the uptake and subsequent metabolism of these energy substrates. Whereas many of these enzymes are regulated through substrate supply and/or energy demand, covalent modification of a number of these enzymes is also important. These regulatory mechanisms mediate substrate utilization and are essential for proper cardiac function.Fatty acids provide a concentrated supply of energy accounting for ϳ50 -75% of the myocardial acetyl CoA-derived ATP (84). Upon entering the cardiac myocyte, fatty acids are transported into the mitochondria and undergo ␤-oxidation to produce acetyl CoA that is eventually used to produce ATP. Glucose is transported into the cell via glucose transporters (GLUT) and can undergo glycolytic metabolism to generate pyruvate and ATP. This can occur in the absence of oxygen while still producing ATP. However, i...

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“…Northern Blotting-Northern hybridizations of MAP1LC3A, MAP1LC3B, and MAP1LC3C were performed on MTN I and MTN II membranes with mRNA samples from 16 adult human tissues as described previously (16). The probes were prepared by labeling the cDNA fragments (amplified from human cDNA libraries as mentioned above) with [␣-32 P]dATP (Amersham Biosciences) using PCR and purified by a Sepharose G50 column.…”

Section: Novel Post-translational Modification Of Human Map1lc3bmentioning

confidence: 99%

Post-translational Modifications of Three Members of the Human MAP1LC3 Family and Detection of a Novel Type of Modification for MAP1LC3B

Dang

Dai

et al. 2003

Journal of Biological Chemistry

Self Cite

268

209

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The molecular machinery required for autophagy is highly conserved in all eukaryotes as seen by the high degree of conservation of proteins involved in the formation of the autophagosome membranes. Recently, both yeast Apg8p and its rat homologue Map1lc3 were identified as essential constituents of autophagosome membrane as a processed form. In addition, both the yeast and human proteins exist in two modified forms produced by a series of post-translational modifications including a critical C-terminal cleavage after a conserved Gly residue, and the smaller processed form is associated with the autophagosome membranes. Herein, we report the identification and characterization of three human orthologs of the rat Map1LC3, named MAP1LC3A, MAP1LC3B, and MAP1LC3C. We show that the three isoforms of human MAP1LC3 exhibit distinct expression patterns in different human tissues. Importantly, we found that the three isoforms of MAP1LC3 differ in their post-translation modifications. Although MAP1LC3A and MAP1LC3C are produced by the proteolytic cleavage after the conserved C-terminal Gly residue, like their rat counterpart, MAP1LC3B does not undergo C-terminal cleavage and exists in a single modified form. The essential site for the distinct posttranslation modification of MAP1LC3B is Lys-122 rather than the conserved Gly-120. Subcellular localization by cell fractionation and immunofluorescence revealed that three human isoforms are associated with membranes involved in the autophagic pathway. These results revealed different regulation of the three human isoforms of MAP1LC3 and implicate that the three isoforms may have different physiological functions.

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Molecular Cloning, Genomic Organization, and Mapping of PRKAG2, a Heart Abundant γ2 Subunit of 5′-AMP-Activated Protein Kinase, to Human Chromosome 7q36

Cited by 57 publications

References 12 publications

Novel PRKAG2 Mutation Responsible for the Genetic Syndrome of Ventricular Preexcitation and Conduction System Disease With Childhood Onset and Absence of Cardiac Hypertrophy

Novel PRKAG2 Mutation Responsible for the Genetic Syndrome of Ventricular Preexcitation and Conduction System Disease With Childhood Onset and Absence of Cardiac Hypertrophy

Role of AMP-activated protein kinase in healthy and diseased hearts

Post-translational Modifications of Three Members of the Human MAP1LC3 Family and Detection of a Novel Type of Modification for MAP1LC3B

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