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Exp Clin Endocrinol Diabetes
DOI: 10.1055/a-2741-4294
Article

Responses of Regulator of G Protein Signaling Proteins and Circadian Clock Components to Sustained Depolarization-Induced Dedifferentiation in MIN6 β-Cells

Authors

  • Satoshi Okano

    1   Graduate School of Medical Science, Yamagata University Faculty of Medicine, Yamagata, Japan

  • Yu Sasaki

    2   Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata, Japan

  • Akira Yasui

    3   Division of Dynamic Proteome in Cancer and Aging, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan

  • Shin-ichiro Kanno

    3   Division of Dynamic Proteome in Cancer and Aging, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan

  • Kennichi Satoh

    4   Division of Gastroenterology, Tohoku Medical and Pharmaceutical University, Sendai, Japan

  • Masahiko Igarashi

    5   Department of Internal Medicine, Takahata Public Hospital, Yamagata, Japan

  • Osamu Nakajima

    1   Graduate School of Medical Science, Yamagata University Faculty of Medicine, Yamagata, Japan

Supported by: IDAC, Tohoku Univ. the Joint Research Program (S.O.)
Supported by: JSPS KAKENHI (19K07498 (S.O.) and 24K11670 (S.O.) )
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Background: Regulators of G protein signaling (RGSs) are key modulators of β-cell function and stress adaptation. Similarly, circadian clock components are intricately implicated in the regulation of insulin secretion and β-cell physiology. However, their responses to sustained cellular stimulation under depolarizing conditions remain incompletely understood. Methods: We used MIN6 cells subjected to prolonged potassium chloride (KCl) exposure to induce sustained membrane depolarization, mimicking conditions of chronic β-cell stimulation. We analyzed the expression levels of Rgs and core clock genes, and assessed associated changes in cellular stress and differentiation markers. Results: KCl treatment led to the upregulation of endoplasmic reticulum (ER) stress markers, including Chop and Atf4, without inducing oxidative stress. Expression of Rgs2, Rgs4, and Rgs16 was elevated. RGS2 partially co-localized with eIF2α, suggesting a role in translational control during stress. Furthermore, KCl-induced depolarization was associated with characteristic changes in β-cell differentiation markers and disallowed genes, indicative of a dedifferentiation-like state. Transcript levels of several circadian genes were altered, including significant downregulation of Dbp and upregulation of its repressor E4bp4. Notably, Dec1, a clock gene known to be inducible by various external stimuli, was also upregulated, suggesting broader circadian disruption under depolarizing conditions. Conclusion: Sustained membrane depolarization induces ER stress and transcriptional remodeling in MIN6 β-cells, including the modulation of RGS proteins and key circadian regulators such as DBP, E4BP4, and DEC1. These alterations may contribute to functional impairment and a dedifferentiation-like state of β-cells under chronic stimulatory conditions.



Publication History

Received: 17 July 2025

Accepted after revision: 07 November 2025

Accepted Manuscript online:
07 November 2025

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