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 Ca(2+) channel alpha(1A) subunit with hereditary neurological disorders. We have identified the ataxic mouse mutation, rolling Nagoya (tg(rol)), in the alpha(1A) gene that leads to a charge-neutralizing arginine-to-glycine substitution at position 1262 in the voltage sensor-forming segment S4 in repeat III. Ca(2+) 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 in tg(rol) mouse cerebella, compared with those in wild-type. Compatible functional change was induced by the tg(rol) mutation in the recombinant alpha(1A) channel, indicating that a defect in voltage sensor of P/Q-type Ca(2+) 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 Ca(2+) 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 alpha(1A) Ca(2+) channel significantly impair integrative properties of Purkinje neurons, presumably resulting in locomotor deficits.
Mori
Y
Y
Department of Information Physiology, National Institute for Physiological Sciences, The Graduate University for Advanced Studies, Okazaki, Aichi, Japan. moriy@nips.ac.jp
Wakamori
M
M
Oda
S
S
Fletcher
C F
CF
Sekiguchi
N
N
Mori
E
E
Copeland
N G
NG
Jenkins
N A
NA
Matsushita
K
K
Matsuyama
Z
Z
Imoto
K
K
D000200:Action Potentials / Q000235:genetics; D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D001259:Ataxia / Q000235:genetics* / Q000503:physiopathology*; D020864:Calcium Channels, N-Type / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D004558:Electric Stimulation; D004594:Electrophysiology; D005260:Female; D015640:Ion Channel Gating / Q000235:genetics; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008809:Mice, Inbred C3H; D008818:Mice, Neurologic Mutants; D010641:Phenotype; D017434:Protein Structure, Tertiary; D011689:Purkinje Cells / Q000737:chemistry / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics
D020864:Calcium Channels, N-Type; D011994:Recombinant Proteins