Frequenin/NCS-1 and the Ca2+-channel α1-subunit co-regulate synaptic transmission and nerve-terminal growth
Frequenin/NCS-1 and the Ca2+-channel α1-subunit co-regulate synaptic transmission and nerve-terminal growth
复制标题
DOI：
10.1242/jcs.055095
复制
发表时间：
2009-11-15
影响因子：
4
通讯作者：
Atwood, Harold L.
中科院分区：
文献类型：
--
作者：
Dason, Jeffrey S.;Romero-Pozuelo, Jesus;Atwood, Harold L.
果蝇Frequenin（Frq）及其哺乳动物和蠕虫同源物NCS-1是参与神经传递的Ca 2+结合蛋白。在果蝇中使用位点特异性重组，我们创建了两个删除，删除了整个frq 1基因和部分frq 2基因，导致检测不到Frq蛋白。Frq无效突变体是可行的，但有缺陷的幼虫运动，缺乏突触传递，受损的Ca 2+进入和增强神经末梢的生长。受损的Ca 2+进入足以解释减少的神经递质释放。我们假设Frq要么调节Ca 2+通道，要么调节PI 4K β途径，如其他生物体中所述。为了确定Frq是否与PI 4K β相互作用，从而对Ca 2+通道产生影响，我们首先表征了PI 4K β无效突变体，并发现PI 4K β对突触传递和神经末端生长具有抑制作用。Frq功能获得性表型仍然存在于PI 4K β无效背景中。我们得出结论，Frq的影响不是由于与PI 4K β的相互作用。使用的果蝇是一个无效的frq等位基因和无效的杂音（编码电压门控钙通道的α（1）-亚基）等位基因的反式杂合，我们显示了这些蛋白质之间的协同效应，在神经递质的释放。功能获得Frq表型被拯救的亚形态杂音突变。总的来说，Frq通过与α（1）电压门控Ca 2+通道亚基的功能性相互作用调节Ca 2+进入;这种相互作用调节神经传递和神经末端生长。
Drosophila Frequenin (Frq) and its mammalian and worm homologue, NCS-1, are Ca2+-binding proteins involved in neurotransmission. Using site-specific recombination in Drosophila, we created two deletions that removed the entire frq1 gene and part of the frq2 gene, resulting in no detectable Frq protein. Frq-null mutants were viable, but had defects in larval locomotion, deficient synaptic transmission, impaired Ca2+ entry and enhanced nerve-terminal growth. The impaired Ca2+ entry was sufficient to account for reduced neurotransmitter release. We hypothesized that Frq either modulates Ca2+ channels, or that it regulates the PI4K beta pathway as described in other organisms. To determine whether Frq interacts with PI4K beta with consequent effects on Ca2+ channels, we first characterized a PI4K beta-null mutant and found that PI4K beta was dispensable for synaptic transmission and nerve-terminal growth. Frq gain-of-function phenotypes remained present in a PI4K beta-null background. We conclude that the effects of Frq are not due to an interaction with PI4K beta. Using flies that were trans-heterozygous for a null frq allele and a null cacophony (encoding the alpha(1)-subunit of voltage-gated Ca2+ channels) allele, we show a synergistic effect between these proteins in neurotransmitter release. Gain-of-function Frq phenotypes were rescued by a hypomorphic cacophony mutation. Overall, Frq modulates Ca2+ entry through a functional interaction with the alpha(1) voltage-gated Ca2+-channel subunit; this interaction regulates neurotransmission and nerve-terminal growth.