Dystrobrevin controls neurotransmitter release and muscle Ca(2+) transients by localizing BK channels in Caenorhabditis elegans.
Dystrobrevin controls neurotransmitter release and muscle Ca(2+) transients by localizing BK channels in Caenorhabditis elegans.
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DOI：
10.1523/jneurosci.3638-11.2011
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发表时间：
2011-11-30
期刊：
影响因子：
--
通讯作者：
Wang ZW
中科院分区：
文献类型：
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作者：
Chen B;Liu P;Zhan H;Wang ZW
Dystrobrevin是肌养蛋白相关蛋白复合物（DAPC）的主要组分。它在哺乳动物组织中广泛表达，包括神经系统，其中它定位于突触前神经末梢，功能未知。在对由C.在elegans中，我们分离了短肌营养不良蛋白基因DYB-1的多个功能丧失（LF）突变体。dyb-1（lf）表型模仿dyb-1（lf），导致神经肌肉接头处神经递质释放增加，体壁肌肉中Ca 2+瞬变频率增加，以及运动行为异常。神经元和肌肉特异性拯救实验表明，DYB-1是神经元和肌肉细胞中SLO-1功能所必需的。DYB-1与SLO-1共定位于神经元的突触前位点和肌细胞的致密体区域，并且dyb-1（lf）引起SLO-1在两种类型的细胞中的错误定位而不改变SLO-1蛋白水平。dyb-1（lf）的神经元表型被小鼠α-dystrobrevin-1（α DB 1）部分挽救。这些观察结果揭示了BK通道在调节肌肉Ca 2+瞬变中的新功能，以及肌养短缩蛋白通过定位BK通道在控制神经递质释放和肌肉Ca 2+瞬变中的新功能。
Dystrobrevin is a major component of a dystrophin-associated protein complex (DAPC). It is widely expressed in mammalian tissues including the nervous system, where it is localized to the presynaptic nerve terminal with unknown function. In a genetic screen for suppressors of a lethargic phenotype caused by a gain-of-function (gf) isoform of SLO-1 in C. elegans, we isolated multiple loss-of-function (lf) mutants of the dystrobrevin gene dyb-1. dyb-1(lf) phenocopied slo-1(lf), causing increased neurotransmitter release at the neuromuscular junction, increased frequency of Ca2+ transients in body-wall muscle, and abnormal locomotion behavior. Neuron- and muscle-specific rescue experiments suggest that DYB-1 is required for SLO-1 function in both neurons and muscle cells. DYB-1 colocalized with SLO-1 at presynaptic sites in neurons and dense body regions in muscle cells, and dyb-1(lf) caused SLO-1 mislocalization in both types of cells without altering SLO-1 protein level. The neuronal phenotypes of dyb-1(lf) were partially rescued by mouse α-dystrobrevin-1 (αDB1). These observations revealed novel functions of the BK channel in regulating muscle Ca2+ transients, and of dystrobrevin in controlling neurotransmitter release and muscle Ca2+ transients by localizing the BK channel.