Reduced Voltage Sensitivity of Activation of P/Q-Type Ca2+Channels is Associated with the Ataxic Mouse MutationRolling Nagoya(tgrol)

Recent genetic analyses have revealed an important association of the gene encoding the P/Q-type voltage-dependent Ca2+channel α1Asubunit with hereditary neurological disorders. We have identified the ataxic mouse mutation,rolling Nagoya(tgrol), in the α1Agene 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 intgrolmouse cerebella, compared with those in wild-type. Compatible functional change was induced by thetgrolmutation in the recombinant α1Achannel, indicating that a defect in voltage sensor of P/Q-type Ca2+channels is the direct consequence of thetgrolmutation. 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, intgrolmice, reduced voltage sensitivity, which may derive from a gating charge defect, and diminished activity of the P-type α1ACa2+channel significantly impair integrative properties of Purkinje neurons, presumably resulting in locomotor deficits.