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Embryonic expression of AMPK ? subunits and the identification of a novel ?2 transcript variant in adult heart.

ABSTRACT: AMP-activated protein kinase (AMPK), the key sensor and regulator of cellular energy status, is a heterotrimeric enzyme with multiple isoforms for each subunit (?1/? 2; ?1/?2; ?1/?2/?3). Mutations in PRKAG2, which encodes the ?2 regulatory subunit, cause a cardiomyopathy characterized by hypertrophy and conduction abnormalities. The two reported PRKAG2 transcript variants, ?2-short and ?2-long (encoding 328 and 569 amino acids respectively), are both widely expressed in adult tissues. We show that both ?2 variants are also expressed during cardiogenesis in mouse embryos; expression of the ?3 isoform was also detected unexpectedly at this stage. As neither ?2 transcript is cardiac specific nor differentially expressed during embryogenesis, it is paradoxical that the disease is largely restricted to the heart. However, a recently annotated ?2 transcript, termed ?2-3B as transcription starts at an alternative exon 3b, has been identified; it is spliced in-frame to exon 4 thus generating a protein of 443 residues in mouse with the first 32 residues being unique. It is increasingly expressed in the developing mouse heart and quantitative PCR analysis established that ?2-3B is the major PRKAG2 transcript (~60%) in human heart. Antibody against the novel N-terminal sequence showed that ?2-3B is predominantly expressed in the heart where it is the most abundant ?2 protein. The abundance of ?2-3B and its tissue specificity indicate that ?2-3B may have non-redundant role in the heart and hence mediate the predominantly cardiac phenotype caused by PRKAG2 mutations.

SUBMITTER: Pinter K

PROVIDER: S-EPMC3477313 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Embryonic expression of AMPK γ subunits and the identification of a novel γ2 transcript variant in adult heart.

Pinter Katalin K Grignani Robert T RT Czibik Gabor G Farza Hend H Watkins Hugh H Redwood Charles C

Journal of molecular and cellular cardiology 20120606 3

AMP-activated protein kinase (AMPK), the key sensor and regulator of cellular energy status, is a heterotrimeric enzyme with multiple isoforms for each subunit (α1/α 2; β1/β2; γ1/γ2/γ3). Mutations in PRKAG2, which encodes the γ2 regulatory subunit, cause a cardiomyopathy characterized by hypertrophy and conduction abnormalities. The two reported PRKAG2 transcript variants, γ2-short and γ2-long (encoding 328 and 569 amino acids respectively), are both widely expressed in adult tissues. We show th ...[more]

PMID: 22683324

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Project description:RationaleAMPK (AMP-activated protein kinase) is a heterotrimeric protein that plays an important role in energy homeostasis and cardioprotection. Two isoforms of each subunit are expressed in the heart, but the isoform-specific function of AMPK remains unclear.ObjectiveWe sought to determine the role of γ2-AMPK in cardiac stress response using bioengineered cell lines and mouse models containing either isoform of the γ-subunit in the heart.Methods and resultsWe found that γ2 but not γ1 or γ3 subunit translocated into nucleus on AMPK activation. Nuclear accumulation of AMPK complexes containing γ2-subunit phosphorylated and inactivated RNA Pol I (polymerase I)-associated transcription factor TIF-IA at Ser-635, precluding the assembly of transcription initiation complexes for rDNA. The subsequent downregulation of pre-rRNA level led to attenuated endoplasmic reticulum (ER) stress and cell death. Deleting γ2-AMPK led to increases in pre-rRNA level, ER stress markers, and cell death during glucose deprivation, which could be rescued by inhibition of rRNA processing or ER stress. To study the function of γ2-AMPK in the heart, we generated a mouse model with cardiac-specific deletion of γ2-AMPK (cardiac knockout [cKO]). Although the total AMPK activity was unaltered in cKO hearts because of upregulation of γ1-AMPK, the lack of γ2-AMPK sensitizes the heart to myocardial ischemia/reperfusion injury. The cKO failed to suppress pre-rRNA level during ischemia/reperfusion and showed a greater infarct size. Conversely, cardiac-specific overexpression of γ2-AMPK decreased ribosome biosynthesis and ER stress during ischemia/reperfusion insult, and the infarct size was reduced.ConclusionsThe γ2-AMPK translocates into the nucleus to suppress pre-rRNA transcription and ribosome biosynthesis during stress, thus ameliorating ER stress and cell death. Increased γ2-AMPK activity is required to protect against ischemia/reperfusion injury. Our study reveals an isoform-specific function of γ2-AMPK in modulating ribosome biosynthesis, cell survival, and cardioprotection.

Dataset Information

Embryonic expression of AMPK ? subunits and the identification of a novel ?2 transcript variant in adult heart.

Publications

Embryonic expression of AMPK γ subunits and the identification of a novel γ2 transcript variant in adult heart.

Similar Datasets

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