Inhaltszusammenfassung

Voltage-gated calcium channels (VGCCs) are crucial for the normal function of excitable cells, and thus, of the nervous system. Correct function of VGCCs depends on their bio-physical properties, localization, and density. In vertebrates, there are 10 genes for the pore-forming α1 subunit, but still, the number of Ca2+ dependent mechanisms seems to largely outcompete the number of VGCC genes. The interaction of high voltage-activated (HVA) α1 subunits with additional accessory subunits, like ...Voltage-gated calcium channels (VGCCs) are crucial for the normal function of excitable cells, and thus, of the nervous system. Correct function of VGCCs depends on their bio-physical properties, localization, and density. In vertebrates, there are 10 genes for the pore-forming α1 subunit, but still, the number of Ca2+ dependent mechanisms seems to largely outcompete the number of VGCC genes. The interaction of high voltage-activated (HVA) α1 subunits with additional accessory subunits, like α2δ, increases the number of functionally different HVA VGCC complexes, but the underlying functional code for α1-α2δ interaction remains incompletely understood. This study aims to unravel the combinato-rial code of functional α1-α2δ interactions by testing whether (i) different α1-α2δ combina-tion serve different or redundant functions, (ii) whether different α2δ subunits modulate distinctly different properties of VGCCs, and (iii) whether different α2δ subunits are spe-cifically required at different subcellular compartments. We use the relatively simpler situation of Drosophila melanogaster, where only 8 instead of the 112 possible vertebrate α1-α2δ-β combinations exist. We further focus our analysis on individually identified mo-toneurons (MNs) with well-described functions for the Drosophila CaV1 and CaV2 homo-logs in different subcellular compartments. Our findings show that both Stj (dα2δ3) and dα2δ1 are expressed in many types of neurons, including MNs, but predominantly localize to different subcellular compartments, thus, indicating functional differences. Electrophysiological analysis demonstrates that Stj is required for correct calcium current amplitudes of both CaV1 and CaV2, while dα2δ1 is not. Stj is required for normal CaV2 current amplitudes at all developmental stages (larva, pupa, and adult) and in all subcellular compartments (somatodendritic, axon & axon ter-minal) of Drosophila MNs. By contrast, dα2δ1 is required for allocation of CaV2 channels specifically to dendrites. Loss of dα2δ1, therefore, results in shifts of dendritic CaV2 chan-nel to the axon. In conclusion, we find that at least Stj and dα2δ1 serve distinctly different functions in the same MNs and are not able to functionally compensate for each other. This contrasts data from heterologous expression systems where redundant functions have been reported, but is in accord with specific α2δ mutations causing different human brain diseases. One possible explanation could be that full functional diversity of α2δ-α1 interactions may unfold only in the brain, because our data hint on functional redundancy of Stj and dα2δ1 in larval muscles. Our findings start unraveling how different α1-α2δ com-binations regulate functional calcium channel diversity in different sub-neuronal com-partments, and may provide an entry point toward understanding how mutations of dif-ferent α2δ genes underlie brain diseases.» weiterlesen» einklappen

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DDC Sachgruppe:
Biowissenschaften, Biologie