Single tottering mutations responsible for the neuropathic phenotype of the P-type calcium channel

Minoru Wakamori, Kazuto Yamazaki, Hiroshi Matsunodaira, Tetsuyuki Teramoto, Isao Tanaka, Tetsuhiro Niidome, Kouhei Sawada, Yukio Nishizawa, Naomi Sekiguchi, Emiko Mori, Yasuo Mori, Keiji Imotot

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200 Citations (Scopus)


Recent genetic and molecular biological analyses have revealed many forms of inherited channelopathies. Homozygous ataxic mice, tottering (tg) and leaner (tg(1a)) mice, have mutations in the P/Q-type Ca2+ channel α(1A) subunit gene. Although their clinical phenotypes, histological changes, and locations of gene mutations are known, it remains unclear what phenotypes the mutant Ca2+ channels manifest, or whether the altered channel properties are the primary consequence of the mutations. To address these questions, we have characterized the electrophysiological properties of Ca2+ channels in cerebellar Purkinje cells, where the P-type is the dominant Ca2+ channel, dissociated from the normal, tg, and tg(1a) mice, and compared them with the properties of the wild-type and mutant α(1A) channels recombinantly expressed with the α2 and β subunits in baby hamster kidney cells. The most striking feature of Ca2+ channel currents of mutant Purkinje cells was a marked reduction in current density, being reduced to ~60 and ~40% of control in tg and tg(1a) mice, respectively, without changes of cell size. The Ca2+ channel currents in the tg Purkinje cells showed a relative increase in non-inactivating component in voltage- dependent inactivation. Besides the same change, those of the tg(1a) mice showed a more distinct change in voltage dependence of activation and inactivation, being shifted in the depolarizing direction by ~10 mV, with a broader voltage dependence of inactivation. In the recombinant expression system, the tg channel with a missense mutation (P601L) and one form of the two possible tg(1a) aberrant splicing products, tg(1a) (short) channel, showed a significant reduction in current density, while the other form of the tg(1a) channels, tg(1a) (long), had a current density comparable to the normal control. On the other hand, the shift in voltage dependence of activation and inactivation was observed only for the tg(1a) (long) channel. Comparison of properties of the native and recombinant mutant channels suggests that single tottering mutations are directly responsible for the neuropathic phenotypes of reduction in current density and deviations in gating behavior, which lead to neuronal death and cerebellar atrophy.

Original languageEnglish
Pages (from-to)34857-34867
Number of pages11
JournalJournal of Biological Chemistry
Issue number52
Publication statusPublished - 1998 Dec 25


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