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Effect of different γ subunit isoforms on the regulation of AMPK

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Title: Effect of different γ subunit isoforms on the regulation of AMPK
Authors: Willows, R
Navaratnam, N
Lima, A
Read, J
Carling, D
Item Type: Journal Article
Abstract: AMP-activated protein kinase (AMPK) plays a key role in integrating metabolic pathways in response to energy demand. AMPK activation results in a wide range of downstream responses, many of which are associated with improved metabolic outcome, making AMPK an attractive target for the treatment of metabolic diseases. AMPK is a heterotrimeric complex consisting of a catalytic subunit (α) and two regulatory subunits (β and γ). The γ-subunit harbours the nucleotide-binding sites and plays an important role in AMPK regulation in response to cellular energy levels. In mammals, there are three isoforms of the γ-subunit and these respond differently to regulation by nucleotides, but there is limited information regarding their role in activation by small molecules. Here, we determined the effect of different γ-isoforms on AMPK by a direct activator, 991. In cells, 991 led to a greater activation of γ2-containing AMPK complexes compared with either γ1 or γ3. This effect was dependent on the long N-terminal region of the γ2-isoform. We were able to rule out an effect of Ser108 phosphorylation, since mutation of Ser108 to alanine in the β2-isoform had no effect on activation of AMPK by 991 in either γ1- or γ2-complexes. The rate of dephosphorylation of Thr172 was slower for γ2- compared with γ1-complexes, both in the absence and presence of 991. Our studies show that activation of AMPK by 991 depends on the nature of the γ-isoform. This finding may have implications for the design of isoform-selective AMPK activators.
Issue Date: 9-May-2017
Date of Acceptance: 16-Mar-2017
URI: http://hdl.handle.net/10044/1/45692
DOI: https://dx.doi.org/10.1042/BCJ20170046
ISSN: 1470-8728
Publisher: Portland Press
Start Page: 1741
End Page: 1754
Journal / Book Title: Biochemical Journal
Volume: 474
Issue: 10
Copyright Statement: © 2017 The Author(s) This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/)
Sponsor/Funder: British Heart Foundation
Funder's Grant Number: FS/13/54/30642
Keywords: AMPK
metabolic regulation
protein–serine–threonine kinases
Biochemistry & Molecular Biology
06 Biological Sciences
11 Medical And Health Sciences
03 Chemical Sciences
Publication Status: Published
Appears in Collections:Clinical Sciences
National Heart and Lung Institute
Molecular Sciences
Faculty of Medicine



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