Abstract

Recent genetic analyses have revealed an important association of the gene encoding the P/Q-type voltage-dependent Ca²⁺ channel α_1A subunit with hereditary neurological disorders. We have identified the ataxic mouse mutation, rolling Nagoya(tg^rol), in the α_1Agene 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 intg^rol mouse cerebella, compared with those in wild-type. Compatible functional change was induced by thetg^rol mutation in the recombinant α_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 α_1ACa²⁺ channel significantly impair integrative properties of Purkinje neurons, presumably resulting in locomotor deficits.