Decreased (45)Ca(2)(+) uptake in P/Q-type calcium channels in homozygous lethargic (Cacnb4lh) mice is associated with increased beta3 and decreased beta4 calcium channel subunit mRNA expression.
The mutated gene in the lethargic (Cacnb4lh) mouse model of absence seizures encodes the beta4 subunit of voltage-gated calcium channels (VGCCs), leading to decreased mRNA expression of a beta4 subunit that is truncated and cannot bind to alpha1 subunits of VGCCs. In this study we accomplished two goals. First, we studied the functional consequence of altered VGCCs by examining the effects of a selective P/Q-type channel antagonist on KCl-induced (45)Ca(2)(+) uptake in brain synaptosomes from Cacnb4lh homozygotes and non-epileptic controls (designated by +/+). We found that depolarization-induced (45)Ca(2)(+) uptake was significantly reduced in the brains of Cacnb4lh homozygotes, and that the reduced uptake was completely accounted for by reduced function of P/Q-type calcium channel. Second, we examined VGCC subunit composition to determine if other subunits were altered in addition to the mutation affecting beta4 subunits in Cacnb4lh homozygotes; when alterations were found, we determined if they were regional or global. We used in situ hybridization histochemistry (ISHH) to analyze the neuro-anatomic distribution of beta4, beta1b, beta2, beta3, alpha1A, alpha1B, alpha1C, alpha1E, and alpha1G subunit mRNAs in brain sections from matched Cacnb4lh homozygotes and +/+ controls. Our results indicated that expression of beta4 subunit mRNA is globally reduced throughout the brains of Cacnb4lh homozygotes, in contrast to a small but significant global increase in the expression of beta3 subunit mRNA. There were no significant differences in expression of the other VGCC subunit mRNAs examined. Together, these findings indicate that a host of changes in VGCC subunit composition accompany reduced function of P/Q-type channels in homozygous lethargic mice.
Lin, F; Barun, S; Lutz, CM; Wang, Y; Hosford, DA
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