L-type calcium channels contribute to the tottering mouse dystonic episodes

Tottering mice inherit a recessive mutation of the calcium channel or,, sub unit that causes ataxia, polyspike discharges, and intermittent dystonic ep isodes. The calcium channel alpha(1A) subunit gene encodes the pore-forming protein of P/Q-type voltage-dependent calcium channels and is predominantl y expressed in cerebellar granule and Purkinje neurons with moderate expres sion in hippocampus and inferior colliculus. Because calcium misregulation likely underlies the tottering mouse phenotype, calcium channel blockers we re tested for their ability to block the motor episodes. Pharmacologic agen ts that specifically block L-type voltage-dependent calcium channels, but n ot P/Q-type calcium channels, prevented the inducible dystonia of tottering mutant mice. Specifically, the dihydropyridines nimodipine, nifedipine, an d nitrendipine, the benzothiazepine diltiazem, and the phenylalkylamine ver apamil all prevented restraint-induced tottering mouse motor episodes. Conv ersely, the L-type calcium channel agonist Bay K8644 induced stereotypic to ttering mouse dystonic at concentrations significantly below those required to induce seizures in control mice. In situ hybridization demonstrated tha t L-type calcium channel or,, subunit mRNA expression was up-regulated in t he Purkinje cells of tottering mice. Radioligand binding with [H-3]nitrendi pine 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 intermitten t dystonia observed in these mice. The susceptibility of L-type calcium cha nnels to voltage-dependent facilitation may promote this abnormal motor phe notype.