title: Anti-Ca2+ channel antibody attenuates Ca2+ currents and mimics cerebellar ataxia in vivo.
abstract: Voltage-gated Ca(2+) channels (VGCCs) are membrane proteins that determine the activity and survival of neurons, and mutations in the P/Q-type VGCCs are known to cause cerebellar ataxia. VGCC dysfunction may also underlie acquired peripheral and central nervous system diseases associated with small-cell lung cancer, including Lambert-Eaton myasthenic syndrome (LEMS) and paraneoplastic cerebellar ataxia (PCA). The pathogenic role of anti-VGCC antibody in LEMS is well established. Although anti-VGCC antibody is also found in a significant fraction of PCA patients, its contribution to PCA is unclear. Using a polyclonal peptide antibody against a major immunogenic region in P/Q-type VGCCs (the extracellular Domain-III S5-S6 loop), we demonstrated that such antibody was sufficient to inhibit VGCC function in neuronal and recombinant VGCCs, alter cerebellar synaptic transmission, and confer the phenotype of cerebellar ataxia. Our data support the hypothesis that anti-VGCC antibody may play a significant role in the pathogenesis of cerebellar dysfunction in PCA.
authors.affiliation: Departments of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. yjliao@stanford.edu
authors.forename: Yaping Joyce
authors.initials: YJ
authors.lastname: Liao
authors.forename: Parsa
authors.initials: P
authors.lastname: Safa
authors.forename: Yi-Ren
authors.initials: YR
authors.lastname: Chen
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Sobel
authors.forename: Edward S
authors.initials: ES
authors.lastname: Boyden
authors.forename: Richard W
authors.initials: RW
authors.lastname: Tsien
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000276:immunology*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D002478:Cells, Cultured; D002524:Cerebellar Ataxia / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D004594:Electrophysiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008855:Microscopy, Electron, Scanning; D018716:Molecular Mimicry; D018408:Patch-Clamp Techniques
chemical_list: D000906:Antibodies; D015220:Calcium Channels; D002118:Calcium