![]() In this work, we assessed the significance of this PM flipping of Stx2 in regulating its i-SNARE action on SG exocytosis. Stx2/epimorphin’s morphogenic property is mediated by its Habc domain 16, not the H3/SNARE domain that interacts with cognate SNARE proteins to mediate fusion 2, 3. This is brought about when intracellular Stx2 flips across the PM, followed by extracellular cleavage at H246 to release the 30-kDa epimorphin 14, 15. ![]() Stx2 exists in three configurations, a full-length form located in both inner and outer PM surface and an extracellularly-truncated form of 30-kDa 15. The 34-kDa Stx2 was better studied as an extracellular morphogen epimorphin involved in epithelial morphogenesis in skin and lung 13, 14. However, the precise mechanism by which Stx2 acts as an i-SNARE remains undefined. Stx2, also an i-SNARE, its deletion promoted insulin SG 11 and pancreatic acinar exocytosis 12. SNAP23, the non-neuronal isoform of SNAP25 that mediates exocytosis in non-neuronal cells, paradoxically acts as an inhibitory SNARE (i-SNARE) in β-cells 9, 10. newcomer is dictated by appropriate pairing of syntaxins (Stx1a for docked, Stx3 for newcomers) and VAMPs (VAMP2 for docked, VAMP8 for newcomers) 5, 6, 7, 8. How insulin SGs are fated to be docked vs. Glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells is characteristically biphasic, with initial peak phase lasting 15 min contributed largely by fusion of docked SGs, and the subsequent phase lasting hours arise from newcomer SGs undergoing minimal residence time at the PM before fusion 4, 5. The cycle of SNARE complex assembly and disassembly is tightly orchestrated by many regulators and chaperones 4. After stimulated SG fusion with PM, the SNARE complex assumes a cis configuration that undergoes disassembly to recycle component SNAREs for another round of SG fusion 2. The SNARE machinery consists of 3 families, vesicle-associated membrane proteins (VAMPs), synaptosomal-associated protein 23/25-kDa and syntaxins (Stxs), which come together in a trans-SNARE complex that docks SGs onto the plasma membrane (PM) in a hemifused state 2, 3. Insulin secretory deficiency in Type-2 diabetes (T2D) is contributed by defective secretory granule (SG) exocytosis attributed to deficiency of soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE) proteins 1. ![]() Here, we show that Stx2 acts to assist this precise tuning of insulin secretion in β-cells, including in diabetes. ![]() ![]() Targeting the flipping efficiency of Stx2 profoundly modulates secretion, which could restore the impaired insulin secretion in diabetes. Using a genetically-encoded reporter, glucose stimulation is shown to induce Stx2 flipping across the plasma membrane, which relieves its suppression of cytoplasmic fusogenic SNARE complexes to promote insulin secretion. Depletion of Stx2 in human β-cells improves insulin secretion by enhancing trans-SNARE complex assembly and cis-SNARE disassembly. We show that excessive Stx2 recruitment to raft-like granule docking sites at higher binding affinity than pro-fusion syntaxin-1A effectively competes for and inhibits fusogenic SNARE machineries. Syntaxin-2 (Stx2) has just been identified to be an inhibitory SNARE for insulin granule exocytosis, holding potential as a treatment for T2D, yet its molecular underpinnings remain unclear. Remote control pairing buttĪfter completing the installation, the system can be checked by running the diagnostic application available at Logitech com/support/Rally.Įnsure that RALLY PLUS is chosen as the camera, speaker, and microphone in your video conferencing applications Please consult the application documentation for further instructions on how to do this.Enhancing pancreatic β-cell secretion is a primary therapeutic target for type-2 diabetes (T2D). ![]()
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