Spinocerebellar ataxia type 6 mutation alters P-type calcium channel function

Shuta Toru, Takayuki Murakoshi, Kinya Ishikawa, Hironao Saegusa, Hiroto Fujigasaki, Toshiki Uchihara, Shin Nagayama, Makoto Osanai, Hidehiro Mizusawa, Tsutomu Tanabe

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97 Citations (Scopus)


Abnormal CAG repeat expansion in the α1A voltage-dependent calcium channel gene is associated with spinocerebellar ataxia type 6, an autosomal dominant cerebellar ataxia with a predominant loss of the Purkinje cell. A reverse transcriptase-polymerase chain reaction analysis of mRNA from mouse Purkinje cells revealed a predominant expression of the α1A channel lacking an asparagine-proline (NP) stretch in the domain IV (α1A(-NP)). Human α1A channels carrying various polyglutamine length with or without NP were expressed in HEK293 cells, and channel properties were compared using a whole-cell voltage clamp technique. α1A(-NP), corresponding to P-type channel, with 24 and 28 polyglutamines found in patients showed the voltage dependence of inactivation shifting negatively by 6 and 11 mV, respectively, from the 13 polyglutamine control. Contrarily, the α1A channel with NP (α1A(+NP)), corresponding to Q-type channel, with 28 polyglutamines exhibited a positive shift of 5 mV. These results suggest that altered function of α1A(-NP) may contribute to degeneration of Purkinje cells, which express predominantly α1A(-NP), due to the reduced Ca2+ influx resulting from the negative shift of voltage-dependent inactivation. On the other hand, other types of neurons, expressing both α1A(-NP) and α1A(+NP), may survive because the positive shift of voltage-dependent inactivation of α1A(+NP) compensates Ca2+ influx.

Original languageEnglish
Pages (from-to)10893-10898
Number of pages6
JournalJournal of Biological Chemistry
Issue number15
Publication statusPublished - 2000 Apr 14

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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