Phosphotidylinositol 4,5-bisphosphate signals underlie receptor-specific Gq/11-mediated modulation of N-type Ca2+ channels
Phosphotidylinositol 4,5-bisphosphate signals underlie receptor-specific Gq/11-mediated modulation of N-type Ca2+ channels
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DOI：
10.1523/jneurosci.3869-04.2004
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发表时间：
2004-12-01
影响因子：
5.3
通讯作者：
Shapiro, MS
中科院分区：
文献类型：
--
作者：
Gamper, N;Reznikov, V;Shapiro, MS
通过G-蛋白偶联受体调节电压门控Ca 2+通道是调节神经递质释放和突触可塑性的主要机制。尽管进行了广泛的研究，但G（q/11）介导的调节的分子机制仍不清楚。我们发现克隆的和天然的N-型钙通道受磷脂酰肌醇4，5-二磷酸（PIP 2）的调节。在由内而外的卵母细胞斑块中，PIP 2极大地减弱或逆转了所观察到的表达通道的下降。在交感神经元，毒蕈碱M-1乙酰胆碱受体抑制的钙电流（I-Ca）的时间与PIP 2水解，钝化的PIP 2在全细胞移液管，衰减的PIP 2螯合蛋白的表达，并成为不可逆的PIP 2合成被阻断时。我们还探讨了受体特异性的机制。虽然缓激肽也诱导PIP 2水解，但它不抑制I-Ca。然而，当PIP 2合成、IP 3受体或神经元Ca 2+传感器-1的活性被阻断时，缓激肽受体变得几乎与M-1受体一样有效，这表明缓激肽受体诱导的细胞内Ca 2+增加刺激PIP 2合成，补偿PIP 2水解。我们认为，PIP 2信号的差异使用是G（q/11）偶联受体对通道作用的特异性的基础。
Modulation of voltage-gated Ca2+ channels via G-protein-coupled receptors is a prime mechanism regulating neurotransmitter release and synaptic plasticity. Despite extensive studies, the molecular mechanism underlying G(q/11)-mediated modulation remains unclear. We found cloned and native N-type Ca2+ channels to be regulated by phosphotidylinositol 4,5-bisphosphate (PIP2). In inside-out oocyte patches, PIP2 greatly attenuated or reversed the observed rundown of expressed channels. In sympathetic neurons, muscarinic M-1 ACh receptor suppression of the Ca2+ current (I-Ca) was temporally correlated with PIP2 hydrolysis, blunted by PIP2 in whole-cell pipettes, attenuated by expression of PIP2-sequestering proteins, and became irreversible when PIP2 synthesis was blocked. We also probed mechanisms of receptor specificity. Although bradykinin also induced PIP2 hydrolysis, it did not inhibit I-Ca. However, bradykinin receptors became nearly as effective as M-1 receptors when PIP2 synthesis, IP3 receptors, or the activity of neuronal Ca2+ sensor-1 were blocked, suggesting that bradykinin receptor-induced intracellular Ca2+ increases stimulate PIP2 synthesis, compensating for PIP2 hydrolysis. We suggest that differential use of PIP2 signals underlies specificity of G(q/11)-coupled receptor actions on the channels.