Direct regulation of BK channels by phosphatidylinositol 4,5-bisphosphate as a novel signaling pathway.
Direct regulation of BK channels by phosphatidylinositol 4,5-bisphosphate as a novel signaling pathway.
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DOI：
10.1085/jgp.200709913
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发表时间：
2008-07
期刊：
影响因子：
--
通讯作者：
Dopico A
中科院分区：
文献类型：
--
作者：
Vaithianathan T;Bukiya A;Liu J;Liu P;Asuncion-Chin M;Fan Z;Dopico A
大电导、钙和电压门控钾（BK）通道普遍存在，对神经元功能、免疫和平滑肌收缩性至关重要。BK通道被认为是由磷脂酰肌醇4,5-二磷酸（PIP2）仅通过磷脂酶C （PLC）产生的PIP2代谢物调控的，PIP2代谢物靶向Ca2+储存和蛋白激酶C，并最终调控BK通道。在这里，我们报道PIP2独立于PIP2代谢物激活BK通道。PIP2增强Ca2+驱动门控，在不影响电压门控和统一电导的情况下改变开通道和闭通道分布。激活后的恢复强烈依赖于PIP2酰基链长度，暴露于水溶性diC4和diC8的通道比暴露于PIP2 （diC16）的通道恢复得快得多。pip2通道相互作用需要负电荷和磷脂头基团中的肌醇部分，以及BK通道形成（cbv1）亚基的S6-S7细胞质连接体中的RKK序列。辅助β1（而非β4）通道亚基显著增强了pip2诱导的激活。此外，PIP2在血管肌细胞中强有力地激活BK通道，β1亚基在血管肌细胞中大量表达，但在骨骼肌细胞中却没有，在骨骼肌细胞中几乎检测不到这些亚基。这些数据表明，最终的PIP2效应是由通道附属亚基决定的，并且这种机制具有亚基特异性。在HEK293细胞中，cbv1+β1和PI4-kinaseIIα共同转染可显著激活BK通道，提示内源性PIP2在调节通道活性中的作用。事实上，在从血管肌细胞切除的膜斑块中，BK通道活性下降，Mg-ATP恢复其活性，这种恢复被应用于细胞质膜表面的PIP2抗体所消除。此外，在生理条件下的完整动脉肌细胞中，PLC的抑制加上下游信号的阻断，导致BK通道的剧烈激活。最后，提高PIP2水平和激活BK通道的药物治疗可以扩张调节脑血流的去内皮动脉。这些数据表明内源性PIP2直接激活血管肌细胞BK通道来控制血管张力。
Large conductance, calcium- and voltage-gated potassium (BK) channels are ubiquitous and critical for neuronal function, immunity, and smooth muscle contractility. BK channels are thought to be regulated by phosphatidylinositol 4,5-bisphosphate (PIP2) only through phospholipase C (PLC)–generated PIP2 metabolites that target Ca2+ stores and protein kinase C and, eventually, the BK channel. Here, we report that PIP2 activates BK channels independently of PIP2 metabolites. PIP2 enhances Ca2+-driven gating and alters both open and closed channel distributions without affecting voltage gating and unitary conductance. Recovery from activation was strongly dependent on PIP2 acyl chain length, with channels exposed to water-soluble diC4 and diC8 showing much faster recovery than those exposed to PIP2 (diC16). The PIP2–channel interaction requires negative charge and the inositol moiety in the phospholipid headgroup, and the sequence RKK in the S6–S7 cytosolic linker of the BK channel-forming (cbv1) subunit. PIP2-induced activation is drastically potentiated by accessory β1 (but not β4) channel subunits. Moreover, PIP2 robustly activates BK channels in vascular myocytes, where β1 subunits are abundantly expressed, but not in skeletal myocytes, where these subunits are barely detectable. These data demonstrate that the final PIP2 effect is determined by channel accessory subunits, and such mechanism is subunit specific. In HEK293 cells, cotransfection of cbv1+β1 and PI4-kinaseIIα robustly activates BK channels, suggesting a role for endogenous PIP2 in modulating channel activity. Indeed, in membrane patches excised from vascular myocytes, BK channel activity runs down and Mg-ATP recovers it, this recovery being abolished by PIP2 antibodies applied to the cytosolic membrane surface. Moreover, in intact arterial myocytes under physiological conditions, PLC inhibition on top of blockade of downstream signaling leads to drastic BK channel activation. Finally, pharmacological treatment that raises PIP2 levels and activates BK channels dilates de-endothelized arteries that regulate cerebral blood flow. These data indicate that endogenous PIP2 directly activates vascular myocyte BK channels to control vascular tone.
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影响因子：
4.8
作者：
Brenner, R;Jegla, TJ;Aldrich, RW
通讯作者：
Aldrich, RW
影响因子：
5.5
作者：
Clarke, AL;Petrou, S;Singer, JJ
通讯作者：
Singer, JJ
影响因子：
20.1
作者：
Jaggar, JH;Li, AL;Leffler, CW
通讯作者：
Leffler, CW
DOI：
10.1152/ajpcell.2001.281.2.c439
发表时间：
2001-08-01
影响因子：
5.5
作者：
Jaggar, JH
通讯作者：
Jaggar, JH
DOI：
10.1085/jgp.20028581
发表时间：
2002-09
期刊：
The Journal of general physiology
影响因子：
--
作者：
Goforth PB;Bertram R;Khan FA;Zhang M;Sherman A;Satin LS
通讯作者：
Satin LS