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β‐arrestins mediate PAR‐2 inhibition of AMPK activity
Author(s) -
wang ping
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.743.11
Subject(s) - ampk , arrestin , protein kinase a , chemistry , microbiology and biotechnology , phosphorylation , amp activated protein kinase , adenosine monophosphate , kinase , signal transduction , adenosine , biology , g protein coupled receptor , biochemistry
Adenosine monophosphate.activated protein kinase (AMPK) plays a key role in energy balance in response to energy depletion. Here we show that the pro‐inflammatory G‐protein coupled receptor, protease‐activated receptor‐2 (PAR‐2), can dually modulate AMPK activity via distinct signaling pathways. In NIH 3T3 cells, activation of PAR‐2 activated AMPK and increased phosphorylation of its substrate, Acc; both events were blocked by overexpression of β‐arrestin‐2. In mouse fat and liver, PAR‐2 only increased AMPK after genetic deletion of β‐arrestin‐2. Suppression of Ca2+/Calmodulin‐Dependent Protein Kinase Kinase‐β (CaMKK‐β) activity with STO‐609 reduced AMPK activity in both NIH3T3 cells and fat tissue from β‐arrestin 2 knockout mice. β‐arrestins associate with AMPK in both primary fat and NIH3T3 cells; this association is increased by PAR‐2 activation. These results indicate that PAR‐2 may positively regulate AMPK activity by through a Ca2+/Gαq‐CaMKKβ pathway in some cells, while inhibiting its activity in others (such as fat and liver) through β‐arrestin‐dependent inhibition of AMPK phosphorylation. These data reveal β‐arrestins can act as molecular switches in cellular energy balance in PAR‐2 actions.