Spinocerebellar ataxia type 6 mutation alters P-type calcium channel function.
Abnormal CAG repeat expansion in the alpha1A 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 alpha1A channel lacking an asparagine-proline (NP) stretch in the domain IV (alpha1A(-NP)). Human alpha1A 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. alpha1A(-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 alpha1A channel with NP (alpha1A(+NP)), corresponding to Q-type channel, with 28 polyglutamines exhibited a positive shift of 5 mV. These results suggest that altered function of alpha1A(-NP) may contribute to degeneration of Purkinje cells, which express predominantly alpha1A(-NP), due to the reduced Ca(2+) influx resulting from the negative shift of voltage-dependent inactivation. On the other hand, other types of neurons, expressing both alpha1A(-NP) and alpha1A(+NP), may survive because the positive shift of voltage-dependent inactivation of alpha1A(+NP) compensates Ca(2+) influx.
Toru
S
S
Department of Neurology and Neurological Science, Japan.
Murakoshi
T
T
Ishikawa
K
K
Saegusa
H
H
Fujigasaki
H
H
Uchihara
T
T
Nagayama
S
S
Osanai
M
M
Mizusawa
H
H
Tanabe
T
T
D000818:Animals; D001483:Base Sequence; D020865:Calcium Channels, P-Type / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D020907:Calcium Channels, Q-Type / Q000235:genetics; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000378:metabolism*; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013132:Spinocerebellar Degenerations / Q000235:genetics*
D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D010455:Peptides; C097188:polyglutamine