Acute treatment with 17β-estradiol attenuates astrocyte–astrocyte and astrocyte–neuron communication

Previous studies showed that 17β-estradiol (17β-E2) regulates the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cGMP pathway in many tissues. Evidence from our laboratory indicates that 17β-E2 disrupts the inhibitory effect of NO on prolactin release, decreasing sGC activity and affecting the cGMP pathway in anterior pituitary gland of adult ovariectomized and estrogenized rats. To ascertain the mechanisms by which 17β-E2 affects sGC activity, we investigated the in vivo and in vitro effects of 17β-E2 on sGC protein and mRNA expression in anterior pituitary gland from immature female rats. In the present work, we showed that 17β-E2 acute treatment exerted opposite effects on the two sGC subunits, increasing α1 and decreasing β1 subunit protein and mRNA expression. This action on sGC protein expression was maximal 6–9 h after 17β-E2 administration. 17β-E2 also caused the same effect on mRNA expression at earlier times. Concomitantly, 17β-E2 dramatically decreased sGC activity 6 and 9 h after injection. These effects were specific of 17β-E2, because they were not observed with the administration of other steroids such as progesterone and 17α-estradiol. This inhibitory action of 17β-E2 on sGC also required the activation of estrogen receptor (ER), because treatment with the pure ER antagonist ICI 182,780 completely blocked 17β-E2 action. 17β-E2 acute treatment caused the same effects on pituitary cells in culture. These results suggest that 17β-E2 exerts an acute inhibitory effect on sGC in anterior pituitary gland by down-regulating sGC β1 subunit and sGC activity in a specific, ER-dependent manner.

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Regulation of Serotonin 1A Receptor SUMOylation by SENP2 and PIASxα

International Journal of Molecular Sciences ◽

10.3390/ijms222413176 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13176

Author(s):

Sugandha Gupta ◽

Mengya Wang ◽

Yoshiaki Azuma ◽

Nancy A. Muma

Keyword(s):

Membrane Fraction ◽

Acute Treatment ◽

Neuropsychiatric Disorders ◽

Depression And Anxiety ◽

Protein Inhibitor ◽

Serotonin 1A Receptor ◽

Cytoplasmic Fraction ◽

Agonist Stimulation ◽

Large Fluctuations ◽

17Β Estradiol

Serotonin 1A receptors (5-HT1ARs) are implicated in the control of mood, cognition, and memory and in various neuropsychiatric disorders such as depression and anxiety. As such, understanding the regulation of 5-HT1ARs will inform the development of better treatment approaches. We previously demonstrated 5-HT1ARs are SUMOylated by SUMO1 in the rat brain. Agonist stimulation increased SUMOylation and was further enhanced when combined with 17β-estradiol-3-benzoate (EB), which are treatments that cause the transient and prolonged desensitization of 5-HT1AR signaling, respectively. In the current study, we identified the protein inhibitor of activated STAT (PIAS)xα as the enzyme that facilitates SUMOylation, and SENP2 as the protein that catalyzes the deSUMOylation of 5-HT1ARs. We demonstrated that PIASxα significantly increased in the membrane fraction of rats co-treated with EB and an agonist, compared to either the EB-treated or vehicle-treated groups. The acute treatment with an agonist alone shifted the location of SENP2 from the membrane to the cytoplasmic fraction, but it has little effect on PIASxα. Hence, two separate mechanisms regulate SUMOylation and the activity of 5-HT1ARs by an agonist and EB. The effects of EB on 5-HT1AR SUMOylation and signaling may be related to the higher incidence of mood disorders in women during times with large fluctuations in estrogens. Targeting the SUMOylation of 5-HT1ARs could have important clinical relevance for the therapy for several neuropsychiatric disorders in which 5-HT1ARs are implicated.

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