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

• Published in: Circulation (New York, N.Y.) Vol. 107; no. 15; pp. 1962 - 1965
• Main Authors: LIGHT, Peter E, WALLACE, Catriona H. R, DYCK, Jason R. B
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 22-04-2003; American Heart Association, Inc
• 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; AMP; Rat; Arrhythmia; Enzyme; Transferases; Rodentia; Electrophysiology; protein kinases; Cardiovascular disease; Heart ventricle; Ionic channel; AMP-activated protein kinase; ion channels; Myocyte; adenosine monophosphate; Vertebrata; Mammalia; Protein kinase; Heart disease; Animal; Sodium ion
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000069269.60167.02

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.