%0 Journal Article %A Laurin Heinrich %A Stefanie Ryglewski %T Different α2δ Accessory Subunits Regulate Distinctly Different Aspects of Calcium Channel Function in the Same Drosophila Neurons %D 2019 %R 10.1101/838565 %J bioRxiv %P 838565 %X Voltage gated calcium channels (VGCCs) regulate neuronal excitability and translate activity into calcium dependent intracellular signaling. The pore forming α1 subunit of high voltage activated (HVA) VGCCs operates not in isolation but associates with α2δ accessory subunits. α2δ subunits can affect calcium channel biophysical properties, surfacing, localization and transport, but their in vivo functions are incompletely understood. In vertebrates, it is largely unknown whether different combinations of the four α2δ and the 7 α1 subunits mediate different or partially redundant functions or whether different α1/α2δ combinations regulate different aspects of VGCC function. This study capitalizes on the relatively simpler situation in the Drosophila genetic model that contains only two genes for HVA calcium channels, one Cav1 homolog and one Cav2 homolog, both with well-described functions in different compartments of identified motoneurons. We find that both dα2δ1 and dα2δ3 (stj) are broadly but differently expressed in the nervous system. Both are expressed in motoneurons, but with differential subcellular localization. Functional analysis reveals that dα2δ3 is required for normal Cav1 and Cav2 current amplitudes and for correct Cav2 channel function in all neuronal compartments, axon terminal, axon, and somatodendritic domain. By contrast, dα2δ1 does not affect Cav1 or Cav2 current amplitudes or presynaptic function, but it is required for correct Cav2 channel allocation to the axonal versus the dendritic domain. Therefore, different α2δ subunits are required in the same neurons to precisely regulate distinctly different functions of HVA calcium channels, which is in accord with specific α2δ mutations causing different brain diseases.Significance Statement Calcium influx through the pore forming α1-subunit of voltage gated calcium channels serves essential neuronal functions, such as synaptic vesicle release, control of action potential shape and frequencies, synaptic input computations, and transcriptional control. Localization and function of α1-calcium channel subunits depend on interactions with α2δ accessory subunits. Here we present in vivo analysis of Drosophila motoneurons revealing that different α2δ subunits independently regulate distinctly different aspects of calcium channel function in the same neuron, such as current amplitude and dendritic versus axonal channel localization. Our findings start unraveling how different α1/α2δ combinations regulate functional calcium channel diversity in different sub-neuronal compartments, and may provide an entry point toward understanding how mutations of different α2δ genes underlie brain diseases. %U https://www.biorxiv.org/content/biorxiv/early/2019/11/12/838565.full.pdf