Abstract
A novel gene (Cacng2; gamma(2)) encoding a protein similar to the voltage-activated Ca(2+) channel gamma(1) subunit was identified as the defective gene in the epileptic and ataxic mouse, stargazer. In this study, we analyzed the association of this novel neuronal gamma(2) subunit with Ca(2+) channels of rabbit brain, and the function of the gamma(2) subunit in recombinant neuronal Ca(2+) channels expressed in Xenopus oocytes. Our results showed that the gamma(2) subunit and a closely related protein (called gamma(3)) co-sedimented and co-immunoprecipitated with neuronal Ca(2+) channel subunits in vivo. Electrophysiological analyses showed that gamma(2) co-expression caused a significant decrease in the current amplitude of both alpha(1B)(alpha(1)2.2)-class (36.8%) and alpha(1A)(alpha(1)2.1)-class (39.7%) Ca(2+) channels (alpha(1)beta(3)alpha(2)delta). Interestingly, the inhibitory effects of the gamma(2) subunit on current amplitude were dependent on the co-expression of the alpha(2)delta subunit. In addition, co-expression of gamma(2) or gamma(1) also significantly decelerates the activation kinetics of alpha(1B)-class Ca(2+) channels. Taken together, these results suggest that the gamma(2) subunit is an important constituent of the neuronal Ca(2+) channel complex and that it down-regulates neuronal Ca(2+) channel activity. Furthermore, the gamma(2) subunit likely contributes to the fine-tuning of neuronal Ca(2+) channels by counterbalancing the effects of the alpha(2)delta subunit.
Highlights
Voltage-activated Ca2ϩ channels play a major role in many fundamental physiological processes including neurotransmission, muscle contraction, intracellular signaling, hormone secretion, and development
By showing the association of the ␥2 subunit with other Ca2ϩ channel subunits, we provide biochemical data supporting the hypothesis that the ␥2 subunit is a component of the neuronal Ca2ϩ channel complex
Interaction of the ␥2 Subunit with the Neuronal Ca2ϩ Channel Complex—In this study, the association of the ␥2 subunit with neuronal Ca2ϩ channel complexes was analyzed through sucrose density gradient fractionation and immunoprecipitation
Summary
Voltage-activated Ca2ϩ channels play a major role in many fundamental physiological processes including neurotransmission, muscle contraction, intracellular signaling, hormone secretion, and development. A similar effect of the ␥2 subunit on current amplitude was observed in oocytes expressing ␣1A-class Ca2ϩ channels (Fig. 2, C and D). The differences in activation at a test potential of Ϫ10 mV are depicted in Fig. 4D using representative normalized current traces from a group of oocytes expressing ␣1B-class channels in the absence and presence of the ␥ subunits.
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