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Stargazing nets new calcium channel subunit

Nature Genetics volume 19, pages 313–314 (1998)Cite this article

On page 340 of this issue2, Verity Lett and colleagues identify the gene mutation that underlies a spontaneously arising form of genetic epilepsy in a mouse mutant called 'stargazer', a name inspired by its distinctive head movement, presumably due to a defect in vestibular function3. The gene encodes a γ subunit of a voltage-sensitive calcium channel (VSCC) and is the first γ subunit known to be expressed in the nervous system. The stargazer mouse is one of several spontaneously arising mutants that exhibit spike-wave epilepsy; the spike-wave electroencephalogram of stargazer closely resembles that observed in humans with absence (or petit-mal) epilepsy. VSCCs constitute a family of diverse proteins that mediate Ca2+ entry through the plasma membrane4, thereby controlling release of neurotransmitters, intracellular signaling pathways and gene expression5. They are composed of an α1 subunit that serves as the membrane pore and voltage sensor. Auxiliary subunits α2, δ and β modulate the kinetics of activation, inactivation, current density and drug binding4. In addition, the presence of the γ subunit in skeletal muscle regulates both the peak currents and rates of activation at more negative potentials6.

The evidence that the Ca2+ channel γ subunit is indeed the mutant protein underlying the stargazer phenotype is compelling. The authors used standard methods to narrow down a chromosomal region previously demonstrated to 'house' the critical gene7, and, upon observing a suspect pattern by Southern blot analysis of 'stargazer' DNA (when compared with wildtype), suspected that insertion of an early transposon might be to blame. Sequence analysis confirmed this suspicion, and defined the 'interrupted' gene, subsequently called Cacng2. Its expression was found to be restricted to the brain, and its coexpression in a cell line stably expressing neuronal α1A VSCCs (alongside α2δ, and β1d) disclosed a negative shift of the voltage dependence of inactivation. This would lead to a significant reduction in channel availability at typical neuronal resting potential. Removal of this effect, as is predicted to be the case in the stargazer mouse, would facilitate Ca2+ entry into the cell -- an effect probably mediated by the interaction of Cacng2 with the other subunits of the VSCC. This observation increases the likelihood that the novel gene is indeed a γ subunit, because the muscle γ subunit exerts a similar effect on some VSCCs.

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Authors and Affiliations

  1. Department of Veterans Affairs Medical Center and Department of Medicine, Division of Neurology, (puranam@neuro.duke.edu), Duke University Medical Center, 401 Bryan Research Building, Research Drive, Durham, 27710, North Carolina, USA

    Ram S Puranam & James O McNamara

  2. Department of Pharmacology and Cancer Biology, (jmc@neuro.duke.edu), Duke University Medical Center, 401 Bryan Research Building, Research Drive, Durham, 27710, North Carolina, USA

    James O McNamara

Authors
  1. Ram S Puranam
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  2. James O McNamara
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Puranam, R., McNamara, J. Stargazing nets new calcium channel subunit. Nat Genet 19, 313–314 (1998). https://doi.org/10.1038/1194

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