Increased Expression of α 1A Ca 2+ Channel Currents Arising from Expanded Trinucleotide Repeats in Spinocerebellar Ataxia Type 6

Erika S. Piedras-Renterı́a; Kei Watase; Nobutoshi Harata; Olga Zhuchenko; Huda Y. Zoghbi; Cheng Chi Lee; Richard W. Tsien

doi:10.1523/JNEUROSCI.21-23-09185.2001

Back

Increased Expression of α 1A Ca 2+ Channel Currents Arising from Expanded Trinucleotide Repeats in Spinocerebellar Ataxia Type 6

Journal article

Open access

Peer reviewed

Increased Expression of α 1A Ca 2+ Channel Currents Arising from Expanded Trinucleotide Repeats in Spinocerebellar Ataxia Type 6

Erika S. Piedras-Renterı́a, Kei Watase, Nobutoshi Harata, Olga Zhuchenko, Huda Y. Zoghbi, Cheng Chi Lee and Richard W. Tsien

The Journal of neuroscience, Vol.21(23), pp.9185-9193

12/01/2001

DOI: 10.1523/JNEUROSCI.21-23-09185.2001

PMCID: PMC6763910

PMID: 11717352

Files and links (1)

url

https://doi.org/10.1523/JNEUROSCI.21-23-09185.2001View

Published (Version of record) Open Access

Abstract

The expansion of polyglutamine tracts encoded by CAG trinucleotide repeats is a common mutational mechanism in inherited neurodegenerative diseases. Spinocerebellar ataxia type 6 (SCA6), an autosomal dominant, progressive disease, arises from trinucleotide repeat expansions present in the coding region of CACNA1A (chromosome 19p13). This gene encodes α1A, the principal subunit of P/Q-type Ca2+ channels, which are abundant in the CNS, particularly in cerebellar Purkinje and granule neurons. We assayed ion channel function by introduction of human α1A cDNAs in human embryonic kidney 293 cells that stably coexpressed β1 and α2δ subunits. Immunocytochemical analysis showed a rise in intracellular and surface expression of α1A protein when CAG repeat lengths reached or exceeded the pathogenic range for SCA6. This gain at the protein level was not a consequence of changes in RNA stability, as indicated by Northern blot analysis. The electrophysiological behavior of α1Asubunits containing expanded (EXP) numbers of CAG repeats (23, 27, and 72) was compared against that of wild-type subunits (WT) (4 and 11 repeats) using standard whole-cell patch-clamp recording conditions. The EXP α1A subunits yielded functional ion channels that supported inward Ca2+ channel currents, with a sharp increase in P/Q Ca2+ channel current density relative to WT. Our results showed that Ca2+channels from SCA6 patients display near-normal biophysical properties but increased current density attributable to elevated protein expression at the cell surface.

Details

Title: Subtitle: Increased Expression of α 1A Ca 2+ Channel Currents Arising from Expanded Trinucleotide Repeats in Spinocerebellar Ataxia Type 6
Creators: Erika S. Piedras-Renterı́a
Kei Watase - Howard Hughes Medical Institute
Nobutoshi Harata - Stanford University
Olga Zhuchenko - Baylor College of Medicine
Huda Y. Zoghbi - Howard Hughes Medical Institute
Cheng Chi Lee - Baylor College of Medicine
Richard W. Tsien - Stanford University
Resource Type: Journal article
Publication Details: The Journal of neuroscience, Vol.21(23), pp.9185-9193
DOI: 10.1523/JNEUROSCI.21-23-09185.2001
PMID: 11717352
PMCID: PMC6763910
NLM abbreviation: J Neurosci
ISSN: 0270-6474
eISSN: 1529-2401
Language: English
Date published: 12/01/2001
Academic Unit: Molecular Physiology and Biophysics
Record Identifier: 9984297508902771

Metrics

6 Record Views

69 Times Cited - Web of Science

See more details