Reduced voltage sensitivity of activation of P/Q-type Ca2+ channels is associated with the ataxic mouse mutation rolling Nagoya (tgrol)

被引:133
作者
Mori, Y [1 ]
Wakamori, M
Oda, S
Fletcher, CF
Sekiguchi, N
Mori, E
Copeland, NG
Jenkins, NA
Matsushita, K
Matsuyama, Z
Imoto, K
机构
[1] Natl Inst Physiol Sci, Dept Informat Physiol, Okazaki, Aichi 4448585, Japan
[2] Grad Univ Adv Studies, Sch Life Sci, Okazaki, Aichi 4448585, Japan
[3] Nagoya Univ, Sch Agr Sci, Lab Anim Management, Nagoya, Aichi 4648601, Japan
[4] NCI, Frederick Canc Res & Dev Ctr, Mammalian Genet Lab, Adv Biosci Labs,Basic Res Program, Frederick, MD 21702 USA
关键词
P/Q-type Ca2+ channel; voltage sensor; gating charge; cerebellar Purkinje cells; ataxia; Ca2+ channel alpha(1A) subunit;
D O I
10.1523/JNEUROSCI.20-15-05654.2000
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Recent genetic analyses have revealed an important association of the gene encoding the P/Q-type voltage-dependent Ca2+ channel alpha(1A) subunit with hereditary neurological disorders. We have identified the ataxic mouse mutation, rolling Nagoya (tg(rol)), in the alpha(1A) gene that leads to a charge-neutralizing arginine-to-glycine substitution at position 1262 in the voltage sensor-forming segment S4 in repeat III. Ca2+ channel currents in acutely dissociated Purkinje cells, where P-type is the dominant type, showed a marked decrease in slope and a depolarizing shift by 8 mV of the conductance-voltage curve and reduction in current density in tg(rol) mouse cerebella, compared with those in wild-type. Compatible functional change was induced by the tg(rol) mutation in the recombinant alpha(1A) channel, indicating that a defect in voltage sensor of P/Q-type Ca2+ channels is the direct consequence of the tg(rol) mutation. Furthermore, somatic whole-cell recording of mutant Purkinje cells displayed only abortive Na+ burst activity and hardly exhibited Ca2+ spike activity in cerebellar slices. Thus, in tg(rol) mice, reduced voltage sensitivity, which may derive from a gating charge defect, and diminished activity of the P-type alpha(1A)Ca(2+) channel significantly impair integrative properties of Purkinje neurons, presumably resulting in locomotor deficits.
引用
收藏
页码:5654 / 5662
页数:9
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