Rocker Is a New Variant of the Voltage-Dependent Calcium Channel Gene Cacna1a

Voltage-gated calcium channels couple changes in membrane potential to neuronal functions regulated by calcium, including neurotransmitter release. Here we report that presynaptic N-type calcium channels not only control neurotransmitter release but also regulate synaptic growth at Drosophila neuromuscular junctions. In a screen for behavioral mutants that disrupt synaptic transmission, an allele of the N-type calcium channel locus (Dmca1A) was identified that caused synaptic undergrowth. The underlying molecular defect was identified as a neutralization of a charged residue in the third S4 voltage sensor. RNA interference reduction of N-type calcium channel expression also reduced synaptic growth. Hypomorphic mutations in syntaxin-1A or n-synaptobrevin, which also disrupt neurotransmitter release, did not affect synapse proliferation at the neuromuscular junction, suggesting calcium entry through presynaptic N-type calcium channels, not neurotransmitter release per se, is important for synaptic growth. The reduced synapse proliferation in Dmca1A mutants is not due to increased synapse retraction but instead reflects a role for calcium influx in synaptic growth mechanisms. These results suggest Ntype channels participate in synaptic growth through signaling pathways that are distinct from those that mediate neurotransmitter release. Linking presynaptic voltage-gated calcium entry to downstream calciumsensitive synaptic growth regulators provides an efficient activity-dependent mechanism for modifying synaptic strength.

Section: Discussionsupporting

confidence: 68%

Section: Fig 4 Synaptic Growth Defects In Dmca1a Nt27mentioning

confidence: 99%

Presynaptic N-type Calcium Channels Regulate Synaptic Growth

Rieckhof

Yoshihara

Guan

et al. 2003

“…They all have a similar phenotype that includes cerebellar ataxia and spike-wave seizures. Tottering (Cacna1a tg ) has a point mutation in Ca V 2.1 (␣ 1 A) (7), and a number of alleles of this mutant have now been identified, as summarized recently (8). Lethargic (Cacnb4 lh ) represents a truncation mutation of the ␤ 4 subunit (9).…”

mentioning

confidence: 99%

The Ducky Mutation in Cacna2d2 Results in Altered Purkinje Cell Morphology and Is Associated with the Expression of a Truncated α2δ-2 Protein with Abnormal Function

Brodbeck¹,

Davies²,

Courtney³

et al. 2002

147

136

The mouse mutant ducky, a model for absence epilepsy, is characterized by spike-wave seizures and cerebellar ataxia. A mutation in Cacna2d2, the gene encoding the ␣2␦-2 voltage-dependent calcium channel accessory subunit, has been found to underlie the ducky phenotype. The ␣2␦-2 mRNA is strongly expressed in cerebellar Purkinje cells. We show that du/du mice have abnormalities in their Purkinje cell dendritic tree. The mutation in ␣2␦-2 results in the introduction of a premature stop codon and predicts the expression of a truncated protein encoded by the first three exons of Cacna2d2, followed by 8 novel amino acids. We show that both mRNA and protein corresponding to this predicted transcript are expressed in du/du cerebellum and present in Purkinje cells. Whereas the ␣2␦-2 subunit increased the peak current density of the Ca V 2.1/␤ 4 channel combination when co-expressed in vitro, co-expression with the truncated mutant ␣2␦-2 protein reduced current density, indicating that it may contribute to the du phenotype.Voltage-gated Ca 2ϩ (Ca V ) 1 channels have been divided functionally into L-, N-, P/Q-, R-, and T-types (1). Each Ca V channel is composed of a pore-forming ␣ 1 subunit, associated at least in the case of the Ca V 1 and -2 subfamilies with an intracellular ␤ subunit responsible for trafficking (2) and a membrane-anchored, but predominantly extracellular, ␣2␦ subunit, whose function is less well defined (2). Ca V 1

“…Similarly, in Ca v 2.1 mouse mutants such as the Rocker mouse, Purkinje neurons show a dramatic reduction of dendritic arborization (52). In contrast, the ␤ 4 lethargic null mutant mouse, which bears the same ataxia and seizure phenotype as the Rocker mouse (probably because of impaired transmitter release in both types of mice), has no apparent structural neuropathology (19,44).…”

Section: Lymnaea Neurons Express a Ca V ␤ Subunit-a Full-lengthmentioning

confidence: 99%

Uncoupling of Calcium Channel α1 and β Subunits in Developing Neurons

Spafford

Minnen

Larsen

et al. 2004

Calcium channel ␤ subunits are key modulators of calcium channel function and membrane targeting of the pore-forming ␣ 1 subunit. Here we show that an invertebrate (Lymnaea stagnalis) homolog of P/Q-and Ntype calcium channels (LCa v 2), although colocalized with ␤ subunits in synapses of mature neurons, is physically uncoupled from the ␤ subunits in the leading edge of growth cones of outgrowing neurons. Moreover, LCa v 2 channels that mediate transmitter release in mature synapses also participate in neuronal outgrowth in growth cones. The differential association of ␤ subunits with synaptic calcium channels and those expressed in emergent neuronal growth suggests that ␤ subunits may play a role in the transformation of Ca v 2 calcium channel function in immature neurons and mature synapses.