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

TY - JOUR

T1 - A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias

AU - Hudson, Emma R.

AU - Pan, David A.

AU - James, John

AU - Lucocq, John M.

AU - Hawley, Simon A.

AU - Green, Kevin A.

AU - Baba, Otto

AU - Terashima, Tatsuo

AU - Hardie, D. Grahame

N1 - dc.publisher: Cell Press

PY - 2003

Y1 - 2003

N2 - 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.

AB - 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.

KW - Cardiac arrhythmias

KW - Protein kinase

KW - Glycogen

U2 - 10.1016/S0960-9822(03)00249-5

DO - 10.1016/S0960-9822(03)00249-5

M3 - Article

SN - 0960-9822

VL - 13

SP - 861

EP - 866

JO - Current Biology

JF - Current Biology

IS - 10

ER -