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(Circulation Research. 2005;97:323.)
© 2005 American Heart Association, Inc.

Molecular Medicine

N488I Mutation of the 2-Subunit Results in Bidirectional Changes in AMP-Activated Protein Kinase Activity

Liqun Zou^*, Mei Shen^*, Michael Arad, Huamei He, Bo Løfgren, Joanne S. Ingwall, Christine E. Seidman, Jon G. Seidman, Rong Tian

From the NMR Laboratory for Physiological Chemistry (L.Z., M.S., H.H., B.L., J.S.I., R.T.), Division of Cardiovascular Medicine (C.E.S.), Brigham and Women’s Hospital, and the Department of Genetics (M.A., C.E.S., J.G.S.), Harvard Medical School, Boston, Mass.

Correspondence to Dr Rong Tian, NMR Laboratory for Physiological Chemistry, 221 Longwood Ave, Rm 252, Boston, MA 02115. E-mail rtian{at}rics.bwh.harvard.edu

Mutations in the human gene encoding the nucleotide-binding region in the -subunit of AMP-activated protein kinase (AMPK) cause cardiomyopathy with preexcitation syndrome. Mutant AMPK showed reduced binding affinity to nucleotides in vitro raising the possibility that altered regulation of AMPK activity by AMP/ATP could contribute to the disease phenotype. In this study, we determined the sensitivity of AMPK activity to AMP/ATP in the beating hearts using transgenic mice expressing a mutant (N488I, 2-mutant) or wild-type 2-subunit (2-TG). The [ATP] and [AMP] were unaltered in all hearts but the AMPK activity was increased by 2.5-fold in 2-mutant hearts freeze-clamped at normal AMP/ATP compared with nontransgenic (WT) or 2-TG. The increased basal AMPK activity was caused by increased Thr-172 phosphorylation of the -subunit (p-AMPK, by 4-fold) at normal [ATP] and was not changed by reducing glycogen content by 60% in the 2-mutant hearts. A reversal of AMP/ATP, caused by ATP degradation, increased p-AMPK by 7-fold in WT but caused no change in 2-mutant hearts. These results demonstrate that the mutation renders AMPK insensitive to the inhibitory and stimulatory effects of the regulatory nucleotides ATP and AMP, respectively, suggesting that the pathogenesis of the human disease may not be attributable to a simple loss- or gain-of-function.

Key Words: AMP-activated protein kinase • heart • magnetic resonance spectroscopy • mouse mutant

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