Dopamine-induced interactions of female mouse hypothalamic proteins with
progestin receptor-A in the absence of hormone.
Authors Acharya KD, Nettles SA, Lichti CF, Warre-Cornish K, Dutan Polit L, Srivastava
DP, Denner L, Tetel MJ
Submitted By Submitted Externally on 10/12/2020
Status Published
Journal Journal of neuroendocrinology, REFERENCES
Year 2020
Date Published 9/1/2020
Volume : Pages Not Specified : e12904
PubMed Reference 33000549
Abstract Neural progestin receptors (PR) function in reproduction, neural development,
neuroprotection, learning, memory and the anxiety response. In the absence of
progestins, PR can be activated by dopamine (DA) in the rodent hypothalamus to
elicit female sexual behaviour. The present study investigated mechanisms of DA
activation of PR by testing the hypothesis that proteins from DA-treated
hypothalami interact with PR in the absence of progestins. Ovariectomised,
oestradiol-primed mice were infused with a D1-receptor agonist, SKF38393 (SKF),
into the third ventricle 30 minutes prior to death. Proteins from SKF-treated
hypothalami were pulled-down with glutathione S-transferase-tagged mouse PR-A or
PR-B and the interactomes were analysed by mass spectrometry. The largest
functional group to interact with PR-A in a DA-dependent manner was synaptic
proteins. To test the hypothesis that DA activation of PR regulates synaptic
proteins, we developed oestradiol-induced PR-expressing hypothalamic-like
neurones derived from human-induced pluripotent stem cells (hiPSCs). Similar to
progesterone (P4), SKF treatment of hiPSCs increased synapsin1/2 expression.
This SKF-dependent effect was blocked by the PR antagonist RU486, suggesting
that PR are necessary for this DA-induced increase. The second largest
DA-dependent PR-A protein interactome comprised metabolic regulators involved in
glucose metabolism, lipid synthesis and mitochondrial energy production.
Interestingly, hypothalamic proteins interacted with PR-A, but not PR-B, in an
SKF-dependent manner, suggesting that DA promotes the interaction of multiple
hypothalamic proteins with PR-A. These in vivo and in vitro results indicate
novel mechanisms by which DA can differentially activate PR isoforms in the
absence of P4 and provide a better understanding of ligand-independent PR
activation in reproductive, metabolic and mental health disorders in women.