Selective serotonin reuptake inhibitor, fluoxetine, impairs E-cadherin-mediated cell adhesion and alters calcium homeostasis in pancreatic beta cells

• Published in: Scientific reports 2017-06, Vol.7 (1), p.3515-13, Article 3515
• Main Authors: Chang, Huang-Yu, Chen, Shu-Ling, Shen, Meng-Ru, Kung, Mei-Lang, Chuang, Lee-Ming, Chen, Yun-Wen
• Format: Article
• Language: English
• Subjects: 14/19; 14/34; 14/35; 38/1; 631/80/79/1902; 631/80/86/1999; 96/109; 96/63; 96/95; Actin; Animals; Antidepressants; Antidepressive Agents, Second-Generation; Beta cells; Cadherins - metabolism; Calcium (intracellular); Calcium (reticular); Calcium - metabolism; Calcium homeostasis; Cell adhesion; Cell adhesion & migration; Cell Adhesion - drug effects; Cell Line; Cytochrome P-450 CYP2D6 Inhibitors; Diabetes mellitus; E-cadherin; Endocytosis; Endoplasmic reticulum; Endoplasmic Reticulum - drug effects; Filaments; Fluorescent Antibody Technique; Fluoxetine; Fluoxetine - metabolism; Homeostasis; Humanities and Social Sciences; Immunofluorescence; Insulin; Insulin secretion; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - physiology; Mice; Mood; multidisciplinary; Pancreas; Science; Science (multidisciplinary); Serotonin uptake inhibitors; Serotonin Uptake Inhibitors - metabolism; STIM1 protein
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-03747-0

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed drugs for mood disorders. Long term use of SSRIs is associated with an increased risk of diabetes, but the underlying mechanism(s) remains elusive. E-cadherin-mediated cell-cell adhesion and elevated [Ca 2+ ] i are important for insulin release and pancreatic β cell functions. This study aims to investigate whether a SSRI, fluoxetine (Prozac), induces pancreatic β cell dysfunction through affecting E-cadherin and/or [Ca 2+ ]i. Here we show that fluoxetine significantly reduces glucose stimulated insulin secretion (GSIS). MIN6 cells, an established murine immortalized β cell line, form smaller colonies of loosely packed cells with reduced cell-cell contact after fluoxetine treatment. Immunofluorescence staining reveals that fluoxetine increases cytoplasmic accumulation of E-cadherin and reduces the membrane-localized E-cadherin probably due to increase of its endocytosis. Fluoxetine inhibits spreading of β cells on E-cad/Fc coated slides and also disrupts E-cadherin-mediated actin filaments. Additionally, fluoxetine significantly suppresses endoplasmic reticulum (ER) calcium release and store-operated calcium entry (SOCE) activation, probably through reduction of ER calcium storage and inhibition of stromal interaction molecule 1 (STIM1) trafficking. These data suggest that exposure to fluoxetine results in impaired β cell functions, occurring in concert with reduction of E-cadherin-dependent cell adhesion and alterations of calcium homeostasis.