Tottering mice inherit a recessive mutation of the calcium channel alpha1A 
subunit that causes ataxia, polyspike discharges, and intermittent dystonic 
episodes. The calcium channel alpha1A subunit gene encodes the pore-forming 
protein of P/Q-type voltage-dependent calcium channels and is predominantly 
expressed in cerebellar granule and Purkinje neurons with moderate expression in 
hippocampus and inferior colliculus. Because calcium misregulation likely 
underlies the tottering mouse phenotype, calcium channel blockers were tested 
for their ability to block the motor episodes. Pharmacologic agents that 
specifically block L-type voltage-dependent calcium channels, but not P/Q-type 
calcium channels, prevented the inducible dystonia of tottering mutant mice. 
Specifically, the dihydropyridines nimodipine, nifedipine, and nitrendipine, the 
benzothiazepine diltiazem, and the phenylalkylamine verapamil all prevented 
restraint-induced tottering mouse motor episodes. Conversely, the L-type calcium 
channel agonist Bay K8644 induced stereotypic tottering mouse dystonic at 
concentrations significantly below those required to induce seizures in control 
mice. In situ hybridization demonstrated that L-type calcium channel alpha1C 
subunit mRNA expression was up-regulated in the Purkinje cells of tottering 
mice. Radioligand binding with [3H]nitrendipine also revealed a significant 
increase in the density of L-type calcium channels in tottering mouse 
cerebellum. These data suggest that although a P/Q-type calcium channel mutation 
is the primary defect in tottering mice, L-type calcium channels may contribute 
to the generation of the intermittent dystonia observed in these mice. The 
susceptibility of L-type calcium channels to voltage-dependent facilitation may 
promote this abnormal motor phenotype.