Editors' ChoiceGestational Diabetes

Insulin Promotes Serotonin Uptake

Sci. Signal.  06 Jan 2015:
Vol. 8, Issue 358, pp. ec1
DOI: 10.1126/scisignal.aaa5978

Gestational diabetes mellitus (GDM) is a common complication of pregnancy that is associated with decreased insulin sensitivity of target tissues, including the placenta. In the periphery, placenta, and developing embryo, serotonin (also known as 5-hydoxytryptamine, 5-HT) functions as a vasoconstrictor. The serotonin concentration in the uteroplacental blood is controlled by serotonin transporters of the SERT family located in the placental trophoblast cells. Li et al. found that trophoblasts from patients with GDM took up less serotonin than those from normal pregnant patients. Flow cytometry and surface biotinylation assays indicated reduced abundance of SERT at the plasma membrane of the GDM-patient trophoblasts. When analyzed by Western blot, GDM-patient trophoblasts had SERT at two molecular weights, the mature size and a lower size corresponding to the size of SERT in normal cells exposed to inhibitors of protein glycosylation, which also showed reduced serotonin uptake. Because these results suggested impaired maturation of SERT in the GDM-patient cells, the authors examined the interaction of SERT with its chaperone ERp44, which binds SERT in the endoplasmic reticulum. Coimmunoprecipitation experiments indicated that the SERT and ERp44 interaction was increased in the cells from the GDM patients compared with that in the cells from the healthy patients. Although insulin receptor abundance was similar in healthy- and GDM-patient cells, tyrosine phosphorylation of the insulin receptor was decreased in GDM-patient cells. Furthermore, trophoblasts from healthy patients showed a dose-dependent increase in serotonin uptake in response to insulin that correlated with an increase in SERT at the plasma membrane, but not with a change in the mRNA abundance for SERT. In healthy patient trophoblasts, but not those from GDM patients, insulin stimulated a reduction in the interaction between ERp44 and SERT. Thus, some of the complications of GDM may arise because of decreased insulin responsiveness of the trophoblasts, which subsequently alters serotonin concentration, thereby impacting blood flow through the placenta.

Y. Li, C. Hadden, P. Singh, C. P. Mercado, P. Murphy, N. K. Dajani, C. L. Lowery, D. J. Roberts, L. Maroteaux, F. Kilic, GDM-associated insulin deficiency hinders the dissociation of SERT from ERp44 and down-regulates placental 5-HT uptake. Proc. Natl. Acad. Sci. U. S. A. 111, E5697–E5705 (2014). [Abstract] [Full Text]