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The mouse stargazer gene encodes a neuronal Ca2+-channel γ subunit

Nature Genetics volume 19, pages 340–347 (1998)Cite this article

Abstract

Stargazer mice have spike-wave seizures characteristic of absence epilepsy, with accompanying defects in the cerebellum and inner ear. We describe here a novel gene, Cacng2, whose expression is disrupted in two stargazer alleles. It encodes a 36-kD protein (stargazin) with structural similarity to the γ subunit of skeletal muscle voltage-gated calcium (Ca2+) channels. Stargazin is brain-specific and, like other neuronal Ca2+-channel subunits, is enriched in synaptic plasma membranes. In vitro, stargazin increases steady-state inactivation of α1 class A Ca2+ channels. The anticipated effect in stargazer mutants, inappropriate Ca2+ entry, may contribute to their more pronounced seizure phenotype compared with other mouse absence models with Ca2+-channel defects. The discovery that the stargazer gene encodes a γ subunit completes the identification of the major subunit types for neuronal Ca2+ channels, namely α1, α2δ, β and γ, providing a new opportunity to understand how these channels function in the mammalian brain and how they may be targeted in the treatment of neuroexcitability disorders.

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Figure 1: An ETn insertion is genetically and physically linked with the stg locus on mouse chromosome 15.
Figure 2: Stargazin protein sequence and similarity to the γ subunit of voltage-gated skeletal muscle Ca2+ channels.
Figure 3: >Stargazin RNA expression in normal and mutant animals.
Figure 4: Stargazin RNA distribution.
Figure 5: Western-blot analysis and immunoprecipitation of stargazin.
Figure 6: Functional effect of stargazin on neuronal Ca2+ channel activity.

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Acknowledgements

We thank P. Nishina for the cDNA library, S. Ackerman, S. Przyborski, J. Gervais, S. Hipkens, A. Costa, G. Yellen, K. Shin, L. Salkoff and R. Coral for advice or assistance at various points in the project and C. Dunbar for expert animal care. We are also grateful to G. Cox and S. Ackerman for review of a preliminary version of this manuscript, and The Jackson Laboratory Mouse Mutant Resource for providing mice. This work was supported by NIH grant NS32801 to V.A.L. and a Klingenstein Fellowship in the Neurosciences to W.N.F. R.F. is supported by a Human Frontier Science Program postdoctoral fellowship. K.P.C. is an investigator of the Howard Hughes Medical Institute. G.H.B. is supported in part by a fellowship from the U. of Iowa Cardiovascular Center.

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Authors and Affiliations

  1. The Jackson Laboratory, Bar Harbor, 04609, Maine, USA

    Verity A. Letts, Connie L. Mahaffey, Alicia Valenzuela & Frederick S. Bartlett II

  2. Department of Physiology and Biophysics and Department of Neurology, Howard Hughes Medical Institute, The University of Iowa College of Medicine, Iowa City, 52242, Iowa, USA

    Ricardo Felix, Gloria H. Biddlecome, Jyothi Arikkath & Kevin P. Campbell

  3. Department of Information Physiology, National Institute for Physiological Sciences, Okazaki, Japan

    Yasuo Mori

  4. Wayne N. Frankel

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  1. Verity A. Letts
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Correspondence to Verity A. Letts or Wayne N. Frankel.

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Letts, V., Felix, R., Biddlecome, G. et al. The mouse stargazer gene encodes a neuronal Ca2+-channel γ subunit. Nat Genet 19, 340–347 (1998). https://doi.org/10.1038/1228

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