مورد إلكتروني
Phosphoinositides control insulin secretion through multiple routes
| العنوان: | Phosphoinositides control insulin secretion through multiple routes |
|---|---|
| بيانات النشر: | Uppsala universitet, Institutionen för medicinsk cellbiologi Uppsala 2020 |
| تفاصيل مُضافة: | Nguyen, Phuoc My |
| نوع الوثيقة: | Electronic Resource |
| مستخلص: | Glucose-stimulated insulin secretion from pancreatic beta cells is the sequence of events that starts with glucose uptake and ends with the fusion of insulin granules with the plasma membrane through Ca2+-triggered exocytosis. Phosphoinositides are minor components of all cellular membranes, yet play fundamental roles as regulators of many cellular processes. PI(4,5)P2 is the most abundant phosphoinositide in the plasma membrane, where it controls the activity of ion channels, endo- and exocytosis and cytoskeletal rearrangements. However, its role in the regulation of insulin secretion is unclear and there are support for both direct stimulatory and inhibitory effects. Using an optogenetic approach to acutely recruit a PI(4,5)P2 phosphatase to deplete the plasma membrane of PI(4,5)P2 in living beta cells, we found that this lipid was required to support voltage-dependent Ca2+-influx and glucose-stimulated insulin secretion. Consistently, depolarization-induced Ca2+-influx was instead augmented when the plasma membrane PI(4,5)P2 concentration was increased by light-dependent recruitment of a PI(4,5)P2-synthesizing enzyme. PI(4)P is another phosphoinositide residing in the plasma membrane and other intracellular membranes. In addition to serving as a precursor for PI(4,5)P2, PI(4)P is used to fuel lipid exchange reactions at membrane contacts sites, such as the PI(4)P/cholesterol exchange at the ER-Golgi interface catalyzed by OSBP. Sac2 is a PI(4)P phosphatase that is highly expressed in neuronal tissues and the pancreas, where it localizes to endosomes and participates in endosome maturation. We found that Sac2 additionally binds to insulin granules through interactions with granule PI(4)P and Rab3. Loss of Sac2 resulted in accumulation of both PI(4)P and cholesterol on the granule surface, impaired insulin granule docking to the plasma membrane and reduced insulin secretion. The cholesterol levels on insulin granules were normalized in cells with reduced OSBP expre |
| مصطلحات الفهرس: | Phosphoinositides, PI(4)P, PI(4, 5)P2, Ca2+, optogenetics, VDCC, Sac2, OSBP, OSW-1, cholesterol, membrane contact sites, Other Medical Sciences, Annan medicin och hälsovetenskap, Doctoral thesis, comprehensive summary, info:eu-repo/semantics/doctoralThesis, text |
| URL: | Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 ; 1713 |
| الإتاحة: | Open access content. Open access content info:eu-repo/semantics/openAccess |
| ملاحظة: | application/pdf English |
| أرقام أخرى: | UPE oai:DiVA.org:uu-429254 urn:isbn:978-91-513-1100-5 1235863525 |
| المصدر المساهم: | UPPSALA UNIV LIBR From OAIster®, provided by the OCLC Cooperative. |
| رقم الأكسشن: | edsoai.on1235863525 |
| قاعدة البيانات: | OAIster |
| الوصف غير متاح. |