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- Title
Kv2.1 Clustering Contributes to Insulin Exocytosis and Rescues Human β-Cell Dysfunction.
- Authors
Jianyang Fu; Xiaoqing Dai; Plummer, Gregory; Kunimasa Suzuki; Bautista, Austin; Githaka, John M.; Senior, Laura; Jensen, Mette; Greitzer-Antes, Dafna; Fox, Jocelyn E. Manning; Gaisano, Herbert Y.; Newgard, Christopher B.; Touret, Nicolas; MacDonald, Patrick E.; Fu, Jianyang; Dai, Xiaoqing; Suzuki, Kunimasa; Manning Fox, Jocelyn E
- Abstract
Insulin exocytosis is regulated by ion channels that control excitability and Ca2+ influx. Channels also play an increasingly appreciated role in microdomain structure. In this study, we examine the mechanism by which the voltage-dependent K+ (Kv) channel Kv2.1 (KCNB1) facilitates depolarization-induced exocytosis in INS 832/13 cells and β-cells from human donors with and without type 2 diabetes (T2D). We find that Kv2.1, but not Kv2.2 (KCNB2), forms clusters of 6-12 tetrameric channels at the plasma membrane and facilitates insulin exocytosis. Knockdown of Kv2.1 expression reduces secretory granule targeting to the plasma membrane. Expression of the full-length channel (Kv2.1-wild-type) supports the glucose-dependent recruitment of secretory granules. However, a truncated channel (Kv2.1-ΔC318) that retains electrical function and syntaxin 1A binding, but lacks the ability to form clusters, does not enhance granule recruitment or exocytosis. Expression of KCNB1 appears reduced in T2D islets, and further knockdown of KCNB1 does not inhibit Kv current in T2D β-cells. Upregulation of Kv2.1-wild-type, but not Kv2.1-ΔC318, rescues the exocytotic phenotype in T2D β-cells and increases insulin secretion from T2D islets. Thus, the ability of Kv2.1 to directly facilitate insulin exocytosis depends on channel clustering. Loss of this structural role for the channel might contribute to impaired insulin secretion in diabetes.
- Subjects
EXOCYTOSIS; INSULIN; CELL physiology; TYPE 2 diabetes; DIABETES; BLOOD sugar; CELL membranes; CYTOPLASM; EPITHELIAL cells; GENETIC techniques; ISLANDS of Langerhans; MEMBRANE proteins; RESEARCH funding; CASE-control method
- Publication
Diabetes, 2017, Vol 66, Issue 7, p1890
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db16-1170