Differential regulation of CaV1.2 channels by cAMP-dependent protein kinase bound to A-kinase anchoring proteins 15 and 79/150.
Differential regulation of CaV1.2 channels by cAMP-dependent protein kinase bound to A-kinase anchoring proteins 15 and 79/150.
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DOI：
10.1085/jgp.201311075
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发表时间：
2014-03
期刊：
影响因子：
--
通讯作者：
Catterall WA
中科院分区：
文献类型：
--
作者：
Fuller MD;Fu Y;Scheuer T;Catterall WA
AKAP 79/150和AKAP 15对CaV 1.2通道具有功能性拮抗作用。CaV1.1和CaV1.2电压门控钙通道启动骨骼肌和心肌细胞中的兴奋-收缩偶联、神经元中的兴奋-转录偶联以及许多其他细胞过程。通过β-肾上腺素能-PKA信号通路上调其活性增加这些生理反应。PKA上调CaV1.2活性可在表达在体内蛋白水解加工位点截短的CaV1.2Δ1800、远端C末端结构域（DCT; CaV1.2[1801-2122]）、CaV1.2通道的辅助α2δ和β亚基以及与DCT中的位点结合的A激酶锚定蛋白15（AKAP 15）的转染细胞系统中重建。AKAP 79/150与AKAP 15结合至DCT中的相同位点。在这里，我们报告说，AKAP 79是无效的支持上调CaV1.2通道活性PKA，即使它结合到DCT中的相同的网站，并抑制上调CaV1.2通道活性AKAP 15支持。AKAP 79（AKAP 79 ΔPIX）中钙调神经磷酸酶结合位点的突变使其支持PKA依赖性CaV 1.2通道活性上调，表明与AKAP 79结合的钙调神经磷酸酶快速使CaV 1.2通道去磷酸化，从而阻止PKA对其的调节。AKAP 15和AKAP 79 ΔPIX通过与DCT中修饰的亮氨酸拉链基序相互作用，对转染细胞中的CaV 1.2通道发挥其调节作用。我们的研究结果介绍了一个意想不到的模式的差异调节AKAPs，其中不同的AKAPs在一个单一的网站的结合可以竞争性地赋予差异调节作用的靶蛋白，通过它们与不同的信号蛋白。
AKAP79/150 and AKAP15 exert functionally antagonistic effects on CaV1.2 channels. The CaV1.1 and CaV1.2 voltage-gated calcium channels initiate excitation-contraction coupling in skeletal and cardiac myocytes, excitation-transcription coupling in neurons, and many other cellular processes. Up-regulation of their activity by the β-adrenergic–PKA signaling pathway increases these physiological responses. PKA up-regulation of CaV1.2 activity can be reconstituted in a transfected cell system expressing CaV1.2Δ1800 truncated at the in vivo proteolytic processing site, the distal C-terminal domain (DCT; CaV1.2[1801–2122]), the auxiliary α2δ and β subunits of CaV1.2 channels, and A-kinase anchoring protein-15 (AKAP15), which binds to a site in the DCT. AKAP79/150 binds to the same site in the DCT as AKAP15. Here we report that AKAP79 is ineffective in supporting up-regulation of CaV1.2 channel activity by PKA, even though it binds to the same site in the DCT and inhibits the up-regulation of CaV1.2 channel activity supported by AKAP15. Mutation of the calcineurin-binding site in AKAP79 (AKAP79ΔPIX) allows it to support PKA-dependent up-regulation of CaV1.2 channel activity, suggesting that calcineurin bound to AKAP79 rapidly dephosphorylates CaV1.2 channels, thereby preventing their regulation by PKA. Both AKAP15 and AKAP79ΔPIX exert their regulatory effects on CaV1.2 channels in transfected cells by interaction with the modified leucine zipper motif in the DCT. Our results introduce an unexpected mode of differential regulation by AKAPs, in which binding of different AKAPs at a single site can competitively confer differential regulatory effects on the target protein by their association with different signaling proteins.
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影响因子：
2.5
作者：
Catterall WA
通讯作者：
Catterall WA
影响因子：
4.8
作者：
Fu, Ying;Westenbroek, Ruth E.;Catterall, William A.
通讯作者：
Catterall, William A.
影响因子：
5
作者：
Hulme, JT;Scheuer, T;Catterall, WA
通讯作者：
Catterall, WA
DOI：
10.1073/pnas.88.23.10778
发表时间：
1991-12-01
影响因子：
11.1
作者：
DEJONGH, KS;WARNER, C;CATTERALL, WA
通讯作者：
CATTERALL, WA
DOI：
10.1073/pnas.93.8.3362
发表时间：
1996-04-16
影响因子：
11.1
作者：
Hell, JW;Westenbroek, RE;Catterall, WA
通讯作者：
Catterall, WA