Constitutively active adenosine monophosphate-activated protein kinase regulates voltage-gated sodium channels in ventricular myocytes

Some PRKAG2 mutations in the human gene encoding for the gamma-subunit of the adenosine monophosphate-activated protein kinase (AMPK) recently have been shown to cause rhythm disturbances (often fatal) in affected patients. Rat ventricular myocytes were infected with an adenoviral vector designed to...

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Bibliographic Details
Published in:Circulation (New York, N.Y.) N.Y.), 2003-04, Vol.107 (15), p.1962-1965
Main Authors: LIGHT, Peter E, WALLACE, Catriona H. R, DYCK, Jason R. B
Format: Article
Language:English
Subjects:
Action Potentials - physiology
Amino Acid Substitution
AMP-Activated Protein Kinases
Animals
Arrhythmias, Cardiac - genetics
Biological and medical sciences
Cardiac dysrhythmias
Cardiology. Vascular system
Cells, Cultured
Enzyme Activation - genetics
Heart
Heart Ventricles - cytology
Humans
Medical sciences
Multienzyme Complexes - genetics
Multienzyme Complexes - metabolism
Myocytes, Cardiac - cytology
Myocytes, Cardiac - metabolism
Patch-Clamp Techniques
Protein Subunits - genetics
Protein Subunits - metabolism
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
Rats
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Sodium Channels - genetics
Sodium Channels - metabolism
Transfection
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Summary:Some PRKAG2 mutations in the human gene encoding for the gamma-subunit of the adenosine monophosphate-activated protein kinase (AMPK) recently have been shown to cause rhythm disturbances (often fatal) in affected patients. Rat ventricular myocytes were infected with an adenoviral vector designed to express a truncated constitutively active mutant (T172D) of the AMPK alpha1-subunit (CA-AMPK). The human cardiac sodium channel hH1 and CA-AMPK were also coexpressed in a mammalian cell line. Patch-clamp techniques were used to measure myocyte action potentials and recombinant hH1 sodium channel currents. Our results demonstrate that action potential duration is significantly prolonged in myocytes expressing the CA-AMPK construct, leading to the production of potentially arrhythmogenic early afterdepolarizations. Recombinant sodium channel current analysis revealed that expression of CA-AMPK significantly slowed open-state inactivation and shifted the voltage-activation curve in a hyperpolarizing direction. We propose that sodium channels may be substrates for AMPK, possibly contributing to the observed arrhythmogenic activity in patients with some PRKAG2 mutations.
ISSN:0009-7322
1524-4539
DOI:10.1161/01.CIR.0000069269.60167.02