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

Yasuo Mori, Minoru Wakamori, Sen Ichi Oda, Colin F. Fletcher, Naomi Sekiguchi, Emiko Mori, Neal G. Copeland, Nancy A. Jenkins, Kaori Matsushita, Zenjiro Matsuyama, Keiji Imoto

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157 Citations (Scopus)

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(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. 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 in tg(rol) mouse cerebella, compared with those in wild-type. Compatible functional change was induced by the tg(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(1A) Ca2+ channel significantly impair integrative properties of Purkinje neurons, presumably resulting in locomotor deficits.

Original languageEnglish
Pages (from-to)5654-5662
Number of pages9
JournalJournal of Neuroscience
Volume20
Issue number15
DOIs
Publication statusPublished - 2000 Aug 1
Externally publishedYes

Keywords

  • Ataxia
  • Ca channel α(1A) subunit
  • Cerebellar Purkinje cells
  • Gating charge
  • P/Q-type Ca channel
  • Voltage sensor

ASJC Scopus subject areas

  • Neuroscience(all)

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    Mori, Y., Wakamori, M., Oda, S. I., Fletcher, C. F., Sekiguchi, N., Mori, E., Copeland, N. G., Jenkins, N. A., Matsushita, K., Matsuyama, Z., & Imoto, K. (2000). Reduced voltage sensitivity of activation of P/Q-type Ca2+ channels is associated with the ataxic mouse mutation rolling Nagoya (tg(rol)). Journal of Neuroscience, 20(15), 5654-5662. https://doi.org/10.1523/jneurosci.20-15-05654.2000