A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias

Emma R. Hudson, David A. Pan, John James, John M. Lucocq, Simon A. Hawley, Kevin A. Green, Otto Baba, Tatsuo Terashima, D. Grahame Hardie

    Research output: Contribution to journalArticlepeer-review

    287 Citations (Scopus)

    Abstract

    The AMP-activated protein kinase (AMPK) is an aß? heterotrimer that is activated by low cellular energy status and affects a switch away from energy-requiring processes and toward catabolism [1]. While it is primarily regulated by AMP and ATP, high muscle glycogen has also been shown to repress its activation [2] and [3]. Mutations in the ?2 and ?3 subunit isoforms lead to arrhythmias associated with abnormal glycogen storage in human heart [4], [5], [6] and [7] and elevated glycogen in pig muscle [8], respectively. A putative glycogen binding domain (GBD) has now been identified in the ß subunits. Coexpression of truncated ß subunits lacking the GBD with a and ? subunits yielded complexes that were active and normally regulated. However, coexpression of a and ? with full-length ß caused accumulation of AMPK in large cytoplasmic inclusions that could be counterstained with anti-glycogen or anti-glycogen synthase antibodies. These inclusions were not affected by mutations that increased or abolished the kinase activity and were not observed by using truncated ß subunits lacking the GBD. Our results suggest that the GBD binds glycogen and can lead to abnormal glycogen-containing inclusions when the kinase is overexpressed. These may be related to the abnormal glycogen storage bodies seen in heart disease patients with ?2 mutations.
    Original languageEnglish
    Pages (from-to)861-866
    Number of pages6
    JournalCurrent Biology
    Volume13
    Issue number10
    DOIs
    Publication statusPublished - 2003

    Keywords

    • Cardiac arrhythmias
    • Protein kinase
    • Glycogen

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