Molecular mechanism of exocytosis from secretory granules that have been trapped into the cortical actin network

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K14647
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 43030:Functional biochemistry-related
• Research Institution: Gunma University
• Principal Investigator: Wang Hao 群馬大学, 生体調節研究所, 助教 (70775874)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: インスリン分泌 / Rabエフェクター / 全反射顕微鏡

Outline of Final Research Achievements

Direct observation of fluorescence-labeled secretory granule exocytosis in living pancreatic β cells has revealed that some granules fuse immediately once they are recruited to the plasma membrane. We show that melanophilin, one of the effectors of the monomeric GTPase Rab27 on the granule membrane, is involved in such an accelerated mode of exocytosis. Both melanophilin-mutated leaden mouse and melanophilin-downregulated human pancreatic β cells exhibit impaired glucose-stimulated insulin secretion, with a specific reduction in fusion events that bypass stable docking to the plasma membrane. Melanophilin mediates this type of fusion by dissociates granules from myosin-5a and actin in the actin cortex and associates them with a fusion-competent, open form of syntaxin-4 on the plasma membrane in stimulus-induced [Ca2+]i rise-dependent manners, which provides the hitherto unknown mechanism to support sustainable exocytosis from granules in the cell interior.

Free Research Field

分子細胞生物学

Academic Significance and Societal Importance of the Research Achievements

安定的な細胞膜ドッキングを介さずに、細胞内部から動員される顆粒からの開口放出は、特にグルコース刺激後期に多く認められ、持続的なインスリン分泌に重要な機構と考えられるが、その分子機序はわかっていなかった。本研究は、その分子機序を明らかにし、今後、刺激依存性に開口放出可能な機能的顆粒プール形成を促進するという、糖尿病の新たな治療戦略とその分子標的を創出・提示する可能性がある。