Selective activation of estrogen receptors modulates electrical activity and insulin secretion in human EndoC-βH1 cells

Estrogen receptors (ERs), ERα and ERβ have important roles in the physiology of the endocrine pancreas in animal models, but the effects of ER activation on insulin-secreting human cells are still poorly understood. Here, we investigated the role of ERα and ERβ as modulators of electrical activity and insulin secretion in the insulin-secreting human cell line EndoC-βH1. Immunocytochemical analysis revealed a widespread cellular distribution of ERα, while ERβ was predominantly localized outside the nucleus. We observed that both estradiol (E2) and the ERβ agonist diarylpropionitrile (DPN) led to a decrease in insulin secretion in the absence of stimulatory glucose concentrations, without affecting insulin content. Patch-clamp experiments revealed that a 48-hour treatment with either the ERα agonist PPT or DPN resulted in depolarization of the resting membrane potential, increased action potential firing frequency, and altered the action potential waveform in EndoC-βH1 cells. PPT increased voltage-dependent Ca 2+ channel currents, while DPN reduced K + and Na + currents. These results suggest that activation of ERα and ERβ modulates beta-cell electrical activity through distinct pathways involving ion channels. The effects of E2, PPT, and DPN were not caused by altered expression levels of ion channel genes after 48 hours of treatment. This suggests that these receptors act extranuclearly without affecting gene expression. Together, our findings demonstrate that selective activation of ERα and ERβ modulates beta-cell excitability through distinct electrophysiological mechanisms and that E2 and DPN reduce basal insulin secretion in human EndoC-βH1 cells. These results support ERα and ERβ as potential targets for modulating human pancreatic beta-cell function.