TAAR1 induces a disturbed GSK3β phosphorylation in recurrent miscarriages through the ODC

Abstract

ObjectivesThyroid hormones play an important role in the maintenance of pregnancy. Their derivates, endogenous amines, act via binding to the trace amine-associated receptor (TAAR1). The aim of our study was to analyse the regulation of TAAR1, serine/threonine kinase (pGSK3β) and ornithine decarboxylase (ODC) in placentas of healthy pregnancies, spontaneous (SM) and recurrent miscarriages (RM) and to investigate the influence of thyroid hormone derivates on TAAR1 expression in trophoblast model cells in vitro.MethodsPatients with SM (n = 15) and RM (n = 15) were compared with patients with healthy pregnancies (n = 15) (pregnancy weeks 7–13 each). Immunohistochemistry was applied to analyse placental TAAR1, pGSK3β and ODC expression. Protein expression of the receptors after stimulation with T3, T1AM and RO5203548 in BeWo trophoblast model cells was determined via Western blot. Double-immunofluorescence was used to determine placental expression of TAAR1 and ODC.ResultsLevels of TAAR1, pGSK3β and ODC were higher in placentas of RM in comparison to healthy controls. Stimulation of BeWo cells with T3, T1AM and RO5203548 significantly increased TAAR1 expression. ODC expression in BeWo cells was upregulated through T3. Via double-immunofluorescence, TAAR1 and ODC-positive EVT could be detected.ConclusionsUpregulation of placental TAAR1 may indicate an increased decarboxylation of thyroid hormones in miscarriages. Patients with RM may have a lack of T3 through an enhanced transformation of T3 into T1AM induced by the ODC. Future investigations could be carried out to analyse what role a prophylactic T3 substitution plays for patients.

Trace Amines and Their Receptors

“…Whether this requires heterodimerization of TAAR1, and if so with what, is an area for further investigation. The authors also provided evidence of TAAR1 agonist-induced increased expression of TAAR1 (Stavrou et al, 2018) suggestive of a positive feedback loop. This is not too dissimilar to the reported elevations of TAAR1 expression in T leukocytes after treatment with methamphetamine (Sriram et al, 2016), itself a TAAR1 agonist.…”

“…Very recently, TAAR1 has been suggested as a novel target for the treatment of miscarriages. An increased expression of TAAR1 was seen in syncytiotrophoblasts, cytotrophoblasts, decidua, and glands of placentas obtained from patients suffering spontaneous or recurrent miscarriages (Stavrou et al, 2018). Furthermore, this increased expression was associated with elevated levels of phosphorylated GSK3b, suggesting elevated b-arrestin 2 signaling.…”

Trace Amine-Associated Receptors as Novel Therapeutic Targets for Immunomodulatory Disorders

“…Given that methamphetamine itself is a TAAR1 agonist ( Bunzow et al, 2001 ; Simmler et al, 2016 ), this raises the possibility of a positive feedback, amplification loop for TAAR1 signaling in T lymphocytes. Such a positive feedback loop has recently been described in response to the highly selective TAAR1 agonist RO5203648 in placental cells ( Stavrou et al, 2018 ).…”

Dopamine synthesis and dopamine receptor expression are disturbed in recurrent miscarriages

“…Immunohistochemistry was performed as described in our recent study by Stavrou et al ( 17 ). After tissue retrieval, tissue samples were fixed in 3.7% formalin and embedded in paraffin.…”

“…Cell line experiments were performed as described by Stavrou et al ( 17 ). The choriocarcinoma cell lines BeWo (ECACC, Salisbury, UK) and JEG-3 (ATCC) were used for the study, which are useful models of human trophoblasts.…”