Untitled

Abstract

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.

The β Subunit of Voltage-Gated Ca2+Channels

“…51, 121, 420, 460, 461, 474). Nevertheless, in lethargic mice, there is increased pairing of Ca v 2.2 and Ca v 2.1 with other Ca v βs; in particular, both β 1b and Ca v 2.2/β 1b complexes are upregulated, similar to what is found in the developing brain (310, 311). Some other characteristics of lethargic mice include lower N-type channel expression in the forebrain and cerebellum (310), reduced excitatory neurotransmission in the thalamus (57), a modified electro-oculogram (301), splenic and thymic involution (130, 131), and renal cysts (130).…”

“…A dynamic and reversible Ca v α 1 -Ca v β association might play an important role in regulating Ca 2+ channel activity, especially during development when changes in the expression level of different Ca v β isoforms occur (311, 435, 449). It has been shown that the Ca v β component of N-type Ca 2+ channels changes during postnatal development, from β 1b > β 3 >> β 2 at P2 to β 3 > β 1b = β 4 at P14 and adult age (449).…”

“…Lethargic mice have ataxia, seizures, absence epilepsy, and paroxysmal dyskinesia (17, 55, 227). The abnormal phenotype appears after postnatal day 15, a time when WT animals have an increase in β 4 expression in the brain (311). The upregulation of β 4 in WT mice is particularly robust in cerebellar granule and Purkinje neurons, which likely explains the ataxia in null mice (55).…”

Altered Expression and Assembly of N-type Calcium Channel α1B and β Subunits in Epileptic lethargic(lh/lh) Mouse

“…Assembly of N-type VDCC subunits has been analyzed in several developing and differentiating systems (15). During IMR32 cell differentiation, ␤1b was up-regulated and increased in parallel with the expression of ␣ 1B (16).…”

Trafficking of neuronal calcium channels

“…Interestingly, although Ca v 1.2 channels are targeted to the soma and dendrites of mature neurons, they are abundantly expressed in the growth cone of developing nerve cells [156]. It is conceivable that this switch in the expression pattern of Ca v 1.2 switch might reflect the existence of a dynamic and reversible association of the channel with different β isoforms [180,181]. Consistent with this notion, a reshuffling of the molecular composition of the N-type channel complex during postnatal development was documented, from β 1b > β 3 >> β 2 at P2 to β 3 > β 1b = β 4 at P14 and the adult stage [182].…”