Reduced voltage sensitivity of activation of P/Q-type Ca2+ channels is associated with the ataxic mouse mutation rolling Nagoya (tg(rol))

Recent genetic analyses have revealed an important association of the gene encoding the P/Q-type voltage-dependent Ca2+ channel alpha(1A) subunit with hereditary neurological disorders. We have identified the ataxic mouse mut ation, rolling Nagoya (tg(rol)), in the alpha(1A) gene that leads to a char ge-neutralizing arginine-to-glycine substitution at position 1262 in the vo ltage sensor-forming segment S4 in repeat III. Ca2+ channel currents in acu tely 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 conducta nce-voltage curve and reduction in current density in tg(rol) mouse cerebel la, compared with those in wild-type. Compatible functional change was indu ced by the tg(rol) mutation in the recombinant alpha(1A) channel, indicatin g that a defect in voltage sensor of P/Q-type Ca2+ channels is the direct c onsequence of the tg(rol) mutation. Furthermore, somatic whole-cell recordi ng 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 d efect, and diminished activity of the P-type alpha(1A)Ca(2+) channel signif icantly impair integrative properties of Purkinje neurons, presumably resul ting in locomotor deficits.