文章基本信息

标题：Giant ankyrin-G: A critical innovation in vertebrate evolution of fast and integrated neuronal signaling
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作者：Paul M. Jenkins ; Namsoo Kim ; Steven L. Jones 等
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：2015
卷号：112
期号：4
页码：957-964
DOI：10.1073/pnas.1416544112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceExcitable axonal membrane microdomains are unique features of vertebrate nervous systems that are required for normal neuronal signaling and are involved in human neurological disorders. Ankyrin-G is a critical adaptor protein that acquired a giant exon early in vertebrate evolution, resulting in a new nervous system-specific polypeptide that is a master organizer of axonal excitable membranes. Giant ankyrin-G-deficient mice live to weaning and provide a rationale for survival of humans with severe cognitive dysfunction bearing a truncating mutation in the giant exon. The giant exon of ankyrin-G thus was a transformative innovation in evolution of the vertebrate nervous system that now is a potential target in neurodevelopmental disorders. Axon initial segments (AISs) and nodes of Ranvier are sites of clustering of voltage-gated sodium channels (VGSCs) in nervous systems of jawed vertebrates that facilitate fast long-distance electrical signaling. We demonstrate that proximal axonal polarity as well as assembly of the AIS and normal morphogenesis of nodes of Ranvier all require a heretofore uncharacterized alternatively spliced giant exon of ankyrin-G (AnkG). This exon has sequence similarity to I-connectin/Titin and was acquired after the first round of whole-genome duplication by the ancestral ANK2/ANK3 gene in early vertebrates before development of myelin. The giant exon resulted in a new nervous system-specific 480-kDa polypeptide combining previously known features of ANK repeats and {beta}-spectrin-binding activity with a fibrous domain nearly 150 nm in length. We elucidate previously undescribed functions for giant AnkG, including recruitment of {beta}4 spectrin to the AIS that likely is regulated by phosphorylation, and demonstrate that 480-kDa AnkG is a major component of the AIS membrane "undercoat' imaged by platinum replica electron microscopy. Surprisingly, giant AnkG-knockout neurons completely lacking known AIS components still retain distal axonal polarity and generate action potentials (APs), although with abnormal frequency. Giant AnkG-deficient mice live to weaning and provide a rationale for survival of humans with severe cognitive dysfunction bearing a truncating mutation in the giant exon. The giant exon of AnkG is required for assembly of the AIS and nodes of Ranvier and was a transformative innovation in evolution of the vertebrate nervous system that now is a potential target in neurodevelopmental disorders.
关键词：neuropsychiatric disease ; cognitive impairment disorder ; axon initial segment ; ankyrin-G ; axonal polarity