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

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 ch...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of neuroscience 2000-08, Vol.20 (15), p.5654
Main Authors: Mori, Yasuo, Wakamori, Minoru, Oda, Sen-ichi, Fletcher, Colin F, Sekiguchi, Naomi, Mori, Emiko, Copeland, Neal G, Jenkins, Nancy A, Matsushita, Kaori, Matsuyama, Zenjiro, Imoto, Keiji
Format: Article
Language:English
Subjects:
Action Potentials - genetics
Alleles
Amino Acid Substitution
Animals
Ataxia - genetics
Ataxia - physiopathology
Calcium Channels, N-Type - chemistry
Calcium Channels, N-Type - genetics
Calcium Channels, N-Type - metabolism
Electric Stimulation
Electrophysiology
Female
Ion Channel Gating - genetics
Male
Mice
Mice, Congenic
Mice, Inbred C3H
Mice, Neurologic Mutants
Phenotype
Protein Structure, Tertiary
Purkinje Cells - chemistry
Purkinje Cells - physiology
Recombinant Proteins - chemistry
Recombinant Proteins - genetics
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.20-15-05654.2000