Stromal Interaction Molecule 1 Maintains β-Cell Identity and Function in Female Mice Through Preservation of G-Protein–Coupled Estrogen Receptor 1 Signaling

dc.contributor.authorSohn, Paul
dc.contributor.authorMcLaughlin, Madeline R.
dc.contributor.authorKrishnan, Preethi
dc.contributor.authorWu, Wenting
dc.contributor.authorSlak Rupnik, Marjan
dc.contributor.authorTakasu, Akira
dc.contributor.authorSenda, Toshiya
dc.contributor.authorLee, Chih-Chun
dc.contributor.authorKono, Tatsuyoshi
dc.contributor.authorEvans-Molina, Carmella
dc.contributor.departmentAnatomy, Cell Biology and Physiology, School of Medicine
dc.date.accessioned2024-03-28T13:41:22Z
dc.date.available2024-03-28T13:41:22Z
dc.date.issued2023
dc.description.abstractAltered endoplasmic reticulum (ER) Ca2+ signaling has been linked with β-cell dysfunction and diabetes development. Store-operated Ca2+ entry replenishes ER Ca2+ through reversible gating of plasma membrane Ca2+ channels by the ER Ca2+ sensor, stromal interaction molecule 1 (STIM1). For characterization of the in vivo impact of STIM1 loss, mice with β-cell-specific STIM1 deletion (STIM1Δβ mice) were generated and challenged with high-fat diet. Interestingly, β-cell dysfunction was observed in female, but not male, mice. Female STIM1Δβ mice displayed reductions in β-cell mass, a concomitant increase in α-cell mass, and reduced expression of markers of β-cell maturity, including MafA and UCN3. Consistent with these findings, STIM1 expression was inversely correlated with HbA1c levels in islets from female, but not male, human organ donors. Mechanistic assays demonstrated that the sexually dimorphic phenotype observed in STIM1Δβ mice was due, in part, to loss of signaling through the noncanonical 17-β estradiol receptor (GPER1), as GPER1 knockdown and inhibition led to a similar loss of expression of β-cell maturity genes in INS-1 cells. Together, these data suggest that STIM1 orchestrates pancreatic β-cell function and identity through GPER1-mediated estradiol signaling.
dc.eprint.versionFinal published version
dc.identifier.citationSohn P, McLaughlin MR, Krishnan P, et al. Stromal Interaction Molecule 1 Maintains β-Cell Identity and Function in Female Mice Through Preservation of G-Protein-Coupled Estrogen Receptor 1 Signaling. Diabetes. 2023;72(10):1433-1445. doi:10.2337/db22-0988
dc.identifier.urihttps://hdl.handle.net/1805/39588
dc.language.isoen_US
dc.publisherAmerican Diabetes Association
dc.relation.isversionof10.2337/db22-0988
dc.relation.journalDiabetes
dc.rightsPublisher Policy
dc.sourcePMC
dc.subjectCalcium channels
dc.subjectEstrogen receptor alpha
dc.subjectMembrane proteins
dc.subjectStromal interaction molecule 1
dc.titleStromal Interaction Molecule 1 Maintains β-Cell Identity and Function in Female Mice Through Preservation of G-Protein–Coupled Estrogen Receptor 1 Signaling
dc.typeArticle
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