Differential expression and association of calcium channel subunits in development and disease

Voltage-gated calcium channels (VDCC) are essential to neuronal maturation and differentiation. It is believed that important signaling information is encoded by VDCC-mediated calcium influx that has both spatial and temporal components. VDCC are multimeric complexes comprised of a pore-forming alpha1 subunit and auxiliary beta and alpha2/delta subunits. Changes in the fractional contribution of distinct calcium conductances to the total calcium current have been noted in developing and differentiating neurons. These changes are anticipated to reflect the differential expression and localization of the pore-forming alpha1 subunits. However, as in vitro studies have established that beta regulates the channel properties and targeting of alpha1, attention has been directed toward the developmental expression and assembly of beta isoforms. Recently, changes in the beta component of the omega-conotoxin GVIA (CTX)-sensitive N-type VDCC have indicated differential assembly of alpha1B with beta in postnatal rat brain. In addition, unique properties of beta4 have been noted with respect to its temporal pattern of expression and incorporation into N-type VDCC complexes. Therefore, the expression and assembly of specific alpha1/beta complexes may reflect an elaborate cellular strategy for regulating VDCC diversity. The importance of these developmental findings is bolstered by a recent study which identified mutations in the beta4 as the molecular defect in the mutant epileptic mouse (lethargic; lh/lh). As beta4 is normally expressed in both forebrain and cerebellum, one may consider the impact of the loss of beta4 upon VDCC assembly and activity. The importance of the beta1b and beta4 isoforms to calcium channel maturation and assembly is discussed.