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The Journal of Neuroscience, August 1, 2000, 20(15):5654-5662

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

Yasuo Mori^{1, 2}, Minoru Wakamori¹, Sen-ichi Oda³, Colin F. Fletcher⁴, Naomi Sekiguchi¹, Emiko Mori¹, Neal G. Copeland⁴, Nancy A. Jenkins⁴, Kaori Matsushita^{1, 2}, Zenjiro Matsuyama¹, and Keiji Imoto^{1, 2}

¹ Department of Information Physiology, National Institute for Physiological Sciences, and ² School of Life Science, The Graduate University for Advanced Studies, Okazaki, Aichi 444-8585, Japan, ³ Laboratory of Animal Management, School of Agricultural Sciences, Nagoya University, Nagoya, Aichi 464-8601, Japan, and ⁴ Mammalian Genetics Laboratory, Advanced Biosciences Labs, Basic Research Program, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland 21702

Recent genetic analyses have revealed an important association of the gene encoding the P/Q-type voltage-dependent Ca²⁺ channel _1A subunit with hereditary neurological disorders. We have identified the ataxic mouse mutation, rolling Nagoya (tg^rol), in the _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 _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 _1A Ca²⁺ channel significantly impair integrative properties of Purkinje neurons, presumably resulting in locomotor deficits.

Key words: P/Q-type Ca²⁺ channel; voltage sensor; gating charge; cerebellar Purkinje cells; ataxia; Ca²⁺ channel _1A subunit

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20155654-09$05.00/0

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