THE MOUSE STARGAZER GENE ENCODES A NEURONAL CA2-CHANNEL GAMMA-SUBUNIT()

Stargazer mice have spike-wave seizures characteristic of absence epil epsy, with accompanying defects in the cerebellum and inner ear. We de scribe here a novel gene, Cacng2, whose expression is disrupted in two stargazer alleles. It encodes a 36-kD protein (stargazin) with struct ural similarity to the gamma-subunit of skeletal muscle voltage-gated calcium (Ca2+) channels. Stargazin is brain-specific and, like other n euronal Ca2+-channel subunits, is enriched in synaptic plasma membrane s. In vitro, stargazin increases steady-state inactivation of alpha(1) class A Ca2+ channels. The anticipated effect in stargazer mutants, i nappropriate Ca2+ entry, may contribute to their more pronounced seizu re phenotype compared with other mouse absence models with Ca2+-channe l defects. The discovery that the stargazer gene encodes a gamma-subun it completes the identification of the major subunit types for neurona l Ca2+ channels, namely alpha(1) alpha(2)delta,beta and gamma, providi ng a new opportunity to understand how these channels function in the mammalian brain and how they may be targeted in the treatment of neuro excitability disorders.