期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2013
卷号：110
期号：43
页码：17576-17581
DOI：10.1073/pnas.1314195110
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Identified over a dozen years ago in the brain and pancreatic islet, {beta}IV-spectrin is critical for the local organization of protein complexes throughout the nervous system. {beta}IV-Spectrin targets ion channels and adapter proteins to axon initial segments and nodes of Ranvier in neurons, and {beta}IV-spectrin dysfunction underlies ataxia and early death in mice. Despite advances in {beta}IV-spectrin research in the nervous system, its role in pancreatic islet biology is unknown. Here, we report that {beta}IV-spectrin serves as a multifunctional structural and signaling platform in the pancreatic islet. We report that {beta}IV-spectrin directly associates with and targets the calcium/calmodulin-dependent protein kinase II (CaMKII) in pancreatic islets. In parallel, {beta}IV-spectrin targets ankyrin-B and the ATP-sensitive potassium channel. Consistent with these findings, {beta}IV-spectrin mutant mice lacking CaMKII- or ankyrin-binding motifs display selective loss of expression and targeting of key protein components, including CaMKII{delta}. {beta}IV-Spectrin-targeted CaMKII directly phosphorylates the inwardly-rectifying potassium channel, Kir6.2 (alpha subunit of KATP channel complex), and we identify the specific residue, Kir6.2 T224, responsible for CaMKII-dependent regulation of KATP channel function. CaMKII-dependent phosphorylation alters channel regulation resulting in KATP channel inhibition, a cellular phenotype consistent with aberrant insulin regulation. Finally, we demonstrate aberrant KATP channel phosphorylation in {beta}IV-spectrin mutant mice. In summary, our findings establish a broader role for {beta}IV-spectrin in regulation of cell membrane excitability in the pancreatic islet, define the pathway for CaMKII local control in pancreatic beta cells, and identify the mechanism for CaMKII-dependent regulation of KATP channels.
