PKG1alpha oxidation negatively regulates food seeking behaviour and reward

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. PKG1alpha can be activated by binding of cyclic guanosine monophosphate (cGMP) or oxidant-induced interprotein disulfide bond for...

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Main Authors:	Duraffourd, Celine, Huckstepp, Robert T. R., Braren, Ingke, Fernandes, Cathy, Brock, Olivier, Delogu, Alessio, Prysyazhna, Oleksandra, Burgoyne, Joseph, Eaton, Philip
Format:	Web Resource
Language:	eng
Subjects:	Food-seeking behaviour Neurosciences & behavior Neurosciences & comportement PKG1alpha Reward Sciences sociales & comportementales, psychologie Social & behavioral sciences, psychology Ventral Tegmental Area
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Summary:	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. PKG1alpha 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. PKG1alpha 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 PKG1alpha knock-in (KI) mice, which are fully deficient in oxidant-induced disulfide-PKG1alpha 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 PKG1alpha oxidation. Indeed, inhibition of monoamine oxidase, which prevents it producing hydrogen peroxide, attenuated PKG1alpha 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 PKG1alpha oxidation providing a break on feeding behaviour. In conclusion, disulfide-PKG1alpha in VTA neurons acts as a negative regulator of feeding and therefore may provide a novel therapeutic target for obesity.
ISSN:	2213-2317 2213-2317