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(Circulation. 2003;107:1962.)
© 2003 American Heart Association, Inc.

Brief Rapid Communications

Constitutively Active Adenosine Monophosphate–Activated Protein Kinase Regulates Voltage-Gated Sodium Channels in Ventricular Myocytes

From the Departments of Pharmacology (P.E.L., C.H.R.W., J.R.B.D.) and Pediatrics (J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.

Correspondence to Peter E. Light, Department of Pharmacology, University of Alberta, 9-58 Medical Sciences, Edmonton, Alberta, Canada T6G 2H7. E-mail peter.light{at}ualberta.ca

Background— Some PRKAG2 mutations in the human gene encoding for the -subunit of the adenosine monophosphate–activated protein kinase (AMPK) recently have been shown to cause rhythm disturbances (often fatal) in affected patients.

Methods and Results— Rat ventricular myocytes were infected with an adenoviral vector designed to express a truncated constitutively active mutant (T172D) of the AMPK ₁-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.

Conclusion— We propose that sodium channels may be substrates for AMPK, possibly contributing to the observed arrhythmogenic activity in patients with some PRKAG2 mutations.

Key Words: AMP-activated protein kinase • protein kinases • adenosine monophosphate • ion channels • arrhythmia

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