TY - JOUR
T1 - PKG1α oxidation negatively regulates food seeking behaviour and reward
AU - Duraffourd, Celine
AU - Huckstepp, Robert T.R.
AU - Braren, Ingke
AU - Fernandes, Cathy
AU - Brock, Olivier
AU - Delogu, Alessio
AU - Prysyazhna, Oleksandra
AU - Burgoyne, Joseph
AU - Eaton, Philip
N1 - Copyright © 2018. Published by Elsevier B.V.
PY - 2019/2/28
Y1 - 2019/2/28
N2 - Genes that are highly conserved in food seeking behaviour, such as protein kinase G (PKG), are of interest because of their potential role in the global obesity epidemic. PKG1α can be activated by binding of cyclic guanosine monophosphate (cGMP) or oxidant-induced interprotein disulfide bond formation between the two subunits of this homodimeric kinase. PKG1α activation by cGMP plays a role in reward and addiction through its actions in the ventral tegmental area (VTA) of the brain. ‘Redox dead’ C42S PKG1α knock-in (KI) mice, which are fully deficient in oxidant-induced disulfide-PKG1α formation, display increased food seeking and reward behaviour compared to wild-type (WT) littermates. Rewarding monoamines such as dopamine, which are released during feeding, are metabolised by monoamine oxidase to generate hydrogen peroxide that was shown to mediate PKG1α oxidation. Indeed, inhibition of monoamine oxidase, which prevents it producing hydrogen peroxide, attenuated PKG1α oxidation and increased sucrose preference in WT, but not KI mice. The deficient reward phenotype of the KI mice was rescued by expressing WT kinase that can form the disulfide state in the VTA using an adeno-associated virus, consistent with PKG1α oxidation providing a break on feeding behaviour. In conclusion, disulfide-PKG1α in VTA neurons acts as a negative regulator of feeding and therefore may provide a novel therapeutic target for obesity.
AB - Genes that are highly conserved in food seeking behaviour, such as protein kinase G (PKG), are of interest because of their potential role in the global obesity epidemic. PKG1α can be activated by binding of cyclic guanosine monophosphate (cGMP) or oxidant-induced interprotein disulfide bond formation between the two subunits of this homodimeric kinase. PKG1α activation by cGMP plays a role in reward and addiction through its actions in the ventral tegmental area (VTA) of the brain. ‘Redox dead’ C42S PKG1α knock-in (KI) mice, which are fully deficient in oxidant-induced disulfide-PKG1α formation, display increased food seeking and reward behaviour compared to wild-type (WT) littermates. Rewarding monoamines such as dopamine, which are released during feeding, are metabolised by monoamine oxidase to generate hydrogen peroxide that was shown to mediate PKG1α oxidation. Indeed, inhibition of monoamine oxidase, which prevents it producing hydrogen peroxide, attenuated PKG1α oxidation and increased sucrose preference in WT, but not KI mice. The deficient reward phenotype of the KI mice was rescued by expressing WT kinase that can form the disulfide state in the VTA using an adeno-associated virus, consistent with PKG1α oxidation providing a break on feeding behaviour. In conclusion, disulfide-PKG1α in VTA neurons acts as a negative regulator of feeding and therefore may provide a novel therapeutic target for obesity.
KW - PKG1α
KW - food-seeking behaviour
KW - reward
KW - Ventral Tegmental Area
U2 - 10.1016/j.redox.2018.101077
DO - 10.1016/j.redox.2018.101077
M3 - Article
C2 - 30593979
SN - 2213-2317
VL - 21
JO - Redox Biology
JF - Redox Biology
M1 - 101077
ER -
