Letts V A, Felix R, Biddlecome G H, Arikkath J, Mahaffey C L, Valenzuela A, Bartlett F S, Mori Y, Campbell K P, Frankel W N
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Nat Genet. 1998 Aug;19(4):340-7. doi: 10.1038/1228.
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 gamma 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 alpha1 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 gamma subunit completes the identification of the major subunit types for neuronal Ca2+ channels, namely alpha1, alpha2delta, beta and gamma, 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.
“凝视者”小鼠具有失神癫痫特有的棘波癫痫发作，同时伴有小脑和内耳缺陷。我们在此描述一个新基因Cacng2，其在两个“凝视者”等位基因中的表达受到破坏。它编码一种36kD的蛋白质（stargazin），与骨骼肌电压门控钙（Ca2+）通道的γ亚基在结构上相似。Stargazin是脑特异性的，并且与其他神经元Ca2+通道亚基一样，在突触质膜中富集。在体外，stargazin增加A类α1型Ca2+通道的稳态失活。与其他具有Ca2+通道缺陷的小鼠失神模型相比，“凝视者”突变体中预期的不适当Ca2+内流效应，可能导致其更明显的癫痫发作表型。“凝视者”基因编码γ亚基这一发现，完成了对神经元Ca2+通道主要亚基类型的鉴定，即α1、α2δ、β和γ，为理解这些通道在哺乳动物大脑中的功能以及在神经兴奋性疾病治疗中如何靶向作用提供了新机会。
