The Journal of Neuroscience, December 1, 2001, 21(23):9185-9193
Increased Expression of 
1A Ca2+
Channel Currents Arising from Expanded Trinucleotide Repeats in
Spinocerebellar Ataxia Type 6
Erika S.
Piedras-Rentería1,
Kei
Watase2, 3,
Nobutoshi
Harata1,
Olga
Zhuchenko2,
Huda Y.
Zoghbi2, 3,
Cheng Chi
Lee2, and
Richard W.
Tsien1
1 Department of Molecular and Cellular Physiology,
Stanford University School of Medicine, Stanford, California 94305, 2 Molecular and Human Genetics, Baylor College of Medicine,
Houston, Texas 77030, and 3 Howard Hughes Medical
Institute, Houston, Texas 77030
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 
1A, 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 1A cDNAs in
human embryonic kidney 293 cells that stably coexpressed
1 and 2
subunits. Immunocytochemical analysis showed a rise in intracellular and surface expression of
1A 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 1A subunits 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 1A 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.
Key words:
P/Q-type calcium channel; 1A; SCA6; polyglutamine; CAG repeats; cerebellar ataxia
Copyright © 2001 Society for Neuroscience 0270-6474/01/21239185-09$05.00/0
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