Original Article

ßIV Spectrin, a New Spectrin Localized at Axon Initial Segments and Nodes of Ranvier in the Central and Peripheral Nervous System

Correspondence to: Michele Solimena, Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, 330 Cedar Street, New Haven, CT 06520. Tel:(203) 737-1037; Fax: (203) 737-2812

We report the identification of ßIV spectrin, a novel spectrin isolated as an interactor of the receptor tyrosine phosphatase-like protein ICA512. The ßIV spectrin gene is located on human and mouse chromosomes 19q13.13 and 7b2, respectively. Alternative splicing of ßIV spectrin generates at least four distinct isoforms, numbered ßIV1–ßIV4 spectrin. The longest isoform (ßIV1 spectrin) includes an actin-binding domain, followed by 17 spectrin repeats, a specific domain in which the amino acid sequence ERQES is repeated four times, several putative SH3-binding sites and a pleckstrin homology domain. ßIV2 and ßIV3 spectrin encompass the NH₂- and COOH-terminal halves of ßIV1 spectrin, respectively, while ßIV4 spectrin lacks the ERQES and the pleckstrin homology domain. Northern blots revealed an abundant expression of ßIV spectrin transcripts in brain and pancreatic islets. By immunoblotting, ßIV1 spectrin is recognized as a protein of 250 kD. Anti–ßIV spectrin antibodies also react with two additional isoforms of 160 and 140 kD. These isoforms differ from ßIV1 spectrin in terms of their distribution on subcellular fractionation, detergent extractability, and phosphorylation. In islets, the immunoreactivity for ßIV spectrin is more prominent in than in ß cells. In brain, ßIV spectrin is enriched in myelinated neurons, where it colocalizes with ankyrin_G 480/270-kD at axon initial segments and nodes of Ranvier. Likewise, ßIV spectrin is concentrated at the nodes of Ranvier in the rat sciatic nerve. In the rat hippocampus, ßIV1 spectrin is detectable from embryonic day 19, concomitantly with the appearance of immunoreactivity at the initial segments. Thus, we suggest that ßIV1 spectrin interacts with ankyrin_G 480/270-kD and participates in the clustering of voltage-gated Na⁺ channels and cell-adhesion molecules at initial segments and nodes of Ranvier.

Key Words: chromosome 19, diabetes, neuropathies, secretion, signal transduction

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