Snapin, a New Regulator of Receptor Signaling, Augments α1A-Adrenoceptor-operated Calcium Influx through TRPC6*
Snapin, a New Regulator of Receptor Signaling, Augments α1A-Adrenoceptor-operated Calcium Influx through TRPC6*
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DOI：
10.1074/jbc.m702063200
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发表时间：
2007-10
影响因子：
4.8
通讯作者：
F. Suzuki;S. Morishima;Takashi Tanaka;I. Muramatsu
中科院分区：
文献类型：
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作者：
F. Suzuki;S. Morishima;Takashi Tanaka;I. Muramatsu
包括α 1A肾上腺素受体（α1A-AR）在内的Gq蛋白偶联受体的激活可通过受体操纵的Ca 2+（ROC）通道引起持续的Ca 2+内流，随后细胞内Ca 2+瞬时释放。瞬时受体电位经典（TRPC）通道是ROC通道的候选蛋白之一，但TRPC介导的Ca 2+内流增加与受体激活之间的确切机制尚不完全清楚。我们确定Snapin是一种与α1A-AR的C末端相互作用的蛋白质。在表达受体的PC 12细胞中，Snapin的共转染通过ROC通道增强了α1A-AR刺激的细胞内Ca 2+（[Ca 2 +]i）的持续增加。通过改变Snapin结合α1A-AR的C-末端结构域或通过用短干扰RNA减少细胞Snapin，在Snapin-α1A-AR共表达的PC 12细胞中[Ca 2 +]i的持续增加被减弱。Snapin与TRPC 6和α1A-AR共免疫沉淀，并且这些相互作用在α1A-AR活化后增强，增加了TRPC 6向细胞表面的募集。我们的数据表明了一种新的受体操作的信号传导机制，其中Snapin将α1A-AR连接到TRPC 6，通过ROC通道增加Ca 2+内流。
Activation of Gq-protein-coupled receptors, including the α1A-adrenoceptor (α1A-AR), causes a sustained Ca2+ influx via receptor-operated Ca2+ (ROC) channels, following the transient release of intracellular Ca2+. Transient receptor potential canonical (TRPC) channel is one of the candidate proteins constituting the ROC channels, but the precise mechanism linking receptor activation to increased influx of Ca2+ via TRPCs is not yet fully understood. We identified Snapin as a protein interacting with the C terminus of the α1A-AR. In receptor-expressing PC12 cells, co-transfection of Snapin augmented α1A-AR-stimulated sustained increases in intracellular Ca2+ ([Ca2+]i) via ROC channels. By altering the Snapin binding C-terminal domain of the α1A-AR or by reducing cellular Snapin with short interfering RNA, the sustained increase in [Ca2+]i in Snapin-α1A-AR co-expressing PC12 cells was attenuated. Snapin co-immunoprecipitated with TRPC6 and α1A-AR, and these interactions were augmented upon α1A-AR activation, increasing the recruitment of TRPC6 to the cell surface. Our data suggest a new receptor-operated signaling mechanism where Snapin links the α1A-AR to TRPC6, augmenting Ca2+ influx via ROC channels.