Imperial College London

ProfessorDavidCarling

Faculty of MedicineInstitute of Clinical Sciences

Professor of Biochemistry
 
 
 
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Contact

 

+44 (0)20 3313 4313david.carling

 
 
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Location

 

3rd Fl CRBHammersmith HospitalHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Willows:2017:10.1042/BCJ20170046,
author = {Willows, R and Navaratnam, N and Lima, A and Read, J and Carling, D},
doi = {10.1042/BCJ20170046},
journal = {Biochemical Journal},
pages = {1741--1754},
title = {Effect of different γ subunit isoforms on the regulation of AMPK},
url = {http://dx.doi.org/10.1042/BCJ20170046},
volume = {474},
year = {2017}
}

RIS format (EndNote, RefMan)

TY  - JOUR
AB - 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.
AU - Willows,R
AU - Navaratnam,N
AU - Lima,A
AU - Read,J
AU - Carling,D
DO - 10.1042/BCJ20170046
EP - 1754
PY - 2017///
SN - 1470-8728
SP - 1741
TI - Effect of different γ subunit isoforms on the regulation of AMPK
T2 - Biochemical Journal
UR - http://dx.doi.org/10.1042/BCJ20170046
UR - http://hdl.handle.net/10044/1/45692
VL - 474
ER -