|Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2000: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1999: ¥2,100,000 (Direct Cost: ¥2,100,000)
An increasing number of disorders have been described in which mutations within voltage-gated ion channels are the underlying molecular defect. Homozygous ataxic mice, tottering (tg) and leaner (tg^<la>) mice, have mutations in the P/Q-type Ca^<2+> channelα_<lA>, subunit gene. Besides these two ataxic mice the third recessive neurological mouse mutant, rolling Nagoya (tg^<rol>), manifests poor motor coordination and stiffness. The rank order of severity of the ataxic symptoms is tg^<la> > tg^<rol> > tg. To explore the relationship between severity of symptoms and channel properties, we have here characterized the electrophysiological properties of Ca^<2+> channels in cerebellar Purkinje cells dissociated from the normal, tg, tg^<la> and tg^<rol> mice. Current density (333 ± 18 pA/pF, n = 67, for normal mice) was significantly reduced in tg^<rol> (247 ± 14, n = 32), tg (184 ± 18, n = 27) and tg^<la> (123 ± 9, n = 25) mice. Peak amplitudes of tail currents, which reflect channel activation, were fitted by a single Boltzmann function, where the voltages for half-maximal activation and slope factors were -28.0 ± 1.1 mV and 4.9 ± 0.5 mV (n = 11) for normal mice, -28.3 ± 1.1 and 4.7 ± 0.3 (n = 13) for tg mice, -20.3 ± 1.7 and 5.8 ± 0.2 (n = 13) for tg^<rol> mice and -19.2 ± 1.3 and 5.4 ± 0.3 (n = 13) for tg^<la> mice, respectively. Activation curves for tg^<rol> and tg^<la> were shifted in the depolarizing direction resulting in reduction of Ca^<2+> channel activity, although it remained normal in tg mice. The results suggest that current reduction and deviation of gating behavior synergically diminish P-type Ca^<2+> channel activity in cerebellar Purkinje cells and may contribute to the neuropathology of the ataxic mice.