Abstract
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.
Highlights
Serotonin (5-HT) and 5-HT1A receptor (5-HT1AR) signaling plays important roles in the pathology and treatment of depression, anxiety, and related mood disorders [1]
To investigate which protein inhibitor of activated STAT (PIAS) proteins are involved in the SUMOylation of 5-HT1ARs, we transfected flag-tagged PIAS constructs into neuroblastoma 2a (N2a) cells
We found that PIASxα is increased in the membrane fraction of paraventricular nucleus of the hypothalamus (PVN) in rats treated with estradiol benzoate (EB) and 8-OH-DPAT, suggesting that this increase in PIASxα is responsible for the increase in 5-HT1ARs SUMOylation induced by EB and 8-OH-DPAT [10]
Summary
Serotonin (5-HT) and 5-HT1A receptor (5-HT1AR) signaling plays important roles in the pathology and treatment of depression, anxiety, and related mood disorders [1]. 5-HT1ARs is essential for the therapeutic effects of antidepressants [3,4]. Women are almost twice as likely to suffer from depression as men, and fluctuations in estrogens contribute to depression and other mood disorders [6]. Estrogens can regulate 5-HT1AR signaling [7]. Our previous study demonstrated that the estrogen 17β-estradiol benzoate (EB) causes a partial desensitization of 5-HT1AR signaling [8] and the combination of the antidepressant fluoxetine and EB produces a robust and rapid desensitization [9]. The mechanisms of this regulation are unclear
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