Abstract
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.
Highlights
Obesity is a major global health problem with 13% of the world’s adult population being affected in 2016
There were no differences between KI mice and WT littermates (WTs) of either sex in overall food consumption (n = 12 or 13 per group; Figure 1aii), showing overall drive to feed is not altered by this mutation
As one by-product of dopamine degradation by monoamine oxidase-B (MAO-B) is hydrogen peroxide [18], we investigated the effect of pharmacologically inhibiting MAO-B on disulfide-PKG1α in WTs
Summary
Obesity is a major global health problem with 13% of the world’s adult population being affected in 2016. Under physiological conditions PKG1α can be regulated by oxidation [6,7,8] Endogenous oxidants, such as hydrogen peroxide, induce a disulfide bond between cysteine 42 on adjacent chains of 2 PKG1α monomers, forming a homodimer complex that renders the kinase catalytically active [6,7,8]. The binding of cGMP to PKG1α attenuates oxidant-induced interprotein disulfide accumulation, perhaps because it causes conformational changes that move the two cysteine 42 residues away from each other[7, 9]. Disulfide-PKG1α dimerisation through oxidation appears to cause a conformational changes in PKG1α that decreases cGMP-dependent activity, which could be due to oxidation lowering affinity for the cyclic nucleotide [2, 10]. The two pathways appear to be antagonistic regulators of PKG1α
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
