Nongenomic Stimulatory Effect of T3 on Calcium Dynamics in GnRH Neurons via Integrin αVβ3.

Abstract

Many clinical studies have identified correlations between thyroid dysfunction and reproductive issues, yet the underlying mechanisms behind this interaction remain poorly understood. In this study, we investigated the effect of triiodothyronine (T3) on the activity of gonadotropin-releasing hormone (GnRH) neurons, a key regulator of the central reproductive axis. Dual labeling confirmed that GnRH neurons express thyroid receptor (TR)α and integrin αVβ3 receptors mediating genomic and nongenomic effects of thyroid hormones, respectively. Using calcium imaging in an ex vivo model, we show that T3 induces a rapid and sustained increase of calcium oscillation frequency in GnRH neurons. No change in response was detected after application of T4. The T3 stimulatory effect was not inhibited by a TR-specific antagonist (1-850) but was mimicked by membrane-impermeable T3-BSA, indicating a mechanism independent of nuclear TR signaling. In contrast, the blockade of membrane αVβ3 integrins (with cilengitide) prevented the T3-induced increase in GnRH neurons calcium peak oscillation frequency. Further investigation using modulators of intracellular calcium and calcium entry revealed that binding to αVβ3 integrin can induce distinct calcium responses depending on the ligand, with T3 triggering a complex response involving multiple channels and calcium sources, possibly with compensatory mechanisms. In sum, these results demonstrate for the first time a direct effect of thyroid hormones on GnRH neuronal activity, with T3 stimulating calcium oscillations through the nongenomic αVβ3 integrin pathway. Understanding this thyroid-reproductive axis interaction will help clarify the mechanisms linking thyroid dysfunction to reproductive disorders and pave the way for targeted therapeutic interventions.