title: Actin dynamics regulated by the balance of neuronal Wiskott-Aldrich syndrome protein (N-WASP) and cofilin activities determines the biphasic response of glucose-induced insulin secretion.
abstract: Actin dynamics in pancreatic β-cells is involved in insulin secretion. However, the molecular mechanisms of the regulation of actin dynamics by intracellular signals in pancreatic β-cells and its role in phasic insulin secretion are largely unknown. In this study, we elucidate the regulation of actin dynamics by neuronal Wiskott-Aldrich syndrome protein (N-WASP) and cofilin in pancreatic β-cells and demonstrate its role in glucose-induced insulin secretion (GIIS). N-WASP, which promotes actin polymerization through activation of the actin nucleation factor Arp2/3 complex, was found to be activated by glucose stimulation in insulin-secreting clonal pancreatic β-cells (MIN6-K8 β-cells). Introduction of a dominant-negative mutant of N-WASP, which lacks G-actin and Arp2/3 complex-binding region VCA, into MIN6-K8 β-cells or knockdown of N-WASP suppressed GIIS, especially the second phase. We also found that cofilin, which severs F-actin in its dephosphorylated (active) form, is converted to the phosphorylated (inactive) form by glucose stimulation in MIN6-K8 β-cells, thereby promoting F-actin remodeling. In addition, the dominant-negative mutant of cofilin, which inhibits activation of endogenous cofilin, or knockdown of cofilin reduced the second phase of GIIS. However, the first phase of GIIS occurs in the G-actin predominant state, in which cofilin activity predominates over N-WASP activity. Thus, actin dynamics regulated by the balance of N-WASP and cofilin activities determines the biphasic response of GIIS.
authors.affiliation: From the Division of Cellular and Molecular Medicine,; the Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, and.
authors.forename: Eita
authors.initials: E
authors.lastname: Uenishi
authors.affiliation: From the Division of Cellular and Molecular Medicine.
authors.forename: Tadao
authors.initials: T
authors.lastname: Shibasaki
authors.affiliation: From the Division of Cellular and Molecular Medicine.
authors.forename: Harumi
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: From the Division of Cellular and Molecular Medicine.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Seki
authors.affiliation: From the Division of Cellular and Molecular Medicine.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Hamaguchi
authors.affiliation: From the Division of Cellular and Molecular Medicine.
authors.forename: Takao
authors.initials: T
authors.lastname: Yasuda
authors.affiliation: From the Division of Cellular and Molecular Medicine.
authors.forename: Masao
authors.initials: M
authors.lastname: Tatebe
authors.affiliation: the Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, and.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Oiso
authors.affiliation: Division of Lipid Biochemistry, and; the Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, Kobe 650-0017.
authors.forename: Tadaomi
authors.initials: T
authors.lastname: Takenawa
authors.affiliation: From the Division of Cellular and Molecular Medicine,; the Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, Kobe 650-0017,; Division of Molecular and Metabolic Medicine,; the Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corp., Kawaguchi, Saitama 332-0012, Japan. Electronic address: seino@med.kobe-u.ac.jp.
authors.forename: Susumu
authors.initials: S
authors.lastname: Seino
mesh_terms: D051339:Actin Depolymerizing Factors / Q000235:genetics / Q000378:metabolism*; D051376:Actin-Related Protein 2-3 Complex / Q000235:genetics / Q000378:metabolism; D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D013549:Sweetening Agents / Q000494:pharmacology*; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000235:genetics / Q000378:metabolism*
chemical_list: D051339:Actin Depolymerizing Factors; D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D007328:Insulin; D013549:Sweetening Agents; C495772:Wasl protein, mouse; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D005947:Glucose
keywords: Actin; Actin Dynamics; Biphasic Insulin Secretion; Cdc42; Cofilin; Glucose-induced Insulin Secretion; Insulin Secretion; N-WASP; β-Cell