Two structural components in CNGA3 support regulation of cone CNG channels by phosphoinositides.
Two structural components in CNGA3 support regulation of cone CNG channels by phosphoinositides.
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DOI：
10.1085/jgp.201210944
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发表时间：
2013-04
期刊：
影响因子：
--
通讯作者：
Varnum MD
中科院分区：
文献类型：
--
作者：
Dai G;Peng C;Liu C;Varnum MD
视网膜光感受器中的环核苷酸门控（CNG）通道在脊椎动物的光转导中起着至关重要的作用。光感受器CNG通道的配体敏感性在适应过程中和响应于旁分泌信号而被调节，但通道调节中涉及的机制仅部分被理解。异聚锥CNGA 3（A3）+CNGB 3（B3）通道被膜磷酸肌醇（PIPn）抑制，包括磷脂酰肌醇3，4，5-三磷酸（PIP 3）和磷脂酰肌醇4，5-二磷酸（PIP 2），表明对环鸟苷一磷酸（cGMP）的表观亲和力降低。与同聚体A1或A2通道不同，A3通道矛盾的是，在PIPn应用后，对cGMP的表观亲和力没有降低。然而，PIPn诱导A3通道的cAMP功效增加2.5倍。cAMP功效的PIPn依赖性变化通过C末端区域的突变（R643 Q/R646 Q）或通过环核苷酸结合结构域远端的截短（613 X）而消除。此外，A3- 613 X揭示了PIPn应用于同源通道时表观cGMP亲和力降低三倍，并且这种效应依赖于A3的N-末端区域内的保守性精氨酸。总之，这些结果表明，A3亚基的磷酸肌醇调控表现出两个可分离的组件，这取决于N-和C-末端区域内的结构元件，分别。此外，A3中的N和C调节模块都支持PIPn对异聚体A3+B3通道的调节。B3亚基不足以赋予PIPn对由PIPn不敏感的A亚基形成的异聚体通道的敏感性。最后，通道形成的PIPn不敏感的A3亚基，在N-和/或C-末端区域互补突变的混合物，恢复PIPn调节，这意味着亚基间N-C相互作用有助于控制锥体CNG通道的磷酸肌醇敏感性。
Cyclic nucleotide-gated (CNG) channels in retinal photoreceptors play a crucial role in vertebrate phototransduction. The ligand sensitivity of photoreceptor CNG channels is adjusted during adaptation and in response to paracrine signals, but the mechanisms involved in channel regulation are only partly understood. Heteromeric cone CNGA3 (A3) + CNGB3 (B3) channels are inhibited by membrane phosphoinositides (PIPn), including phosphatidylinositol 3,4,5-triphosphate (PIP3) and phosphatidylinositol 4,5-bisphosphate (PIP2), demonstrating a decrease in apparent affinity for cyclic guanosine monophosphate (cGMP). Unlike homomeric A1 or A2 channels, A3-only channels paradoxically did not show a decrease in apparent affinity for cGMP after PIPn application. However, PIPn induced an ∼2.5-fold increase in cAMP efficacy for A3 channels. The PIPn-dependent change in cAMP efficacy was abolished by mutations in the C-terminal region (R643Q/R646Q) or by truncation distal to the cyclic nucleotide-binding domain (613X). In addition, A3-613X unmasked a threefold decrease in apparent cGMP affinity with PIPn application to homomeric channels, and this effect was dependent on conserved arginines within the N-terminal region of A3. Together, these results indicate that regulation of A3 subunits by phosphoinositides exhibits two separable components, which depend on structural elements within the N- and C-terminal regions, respectively. Furthermore, both N and C regulatory modules in A3 supported PIPn regulation of heteromeric A3+B3 channels. B3 subunits were not sufficient to confer PIPn sensitivity to heteromeric channels formed with PIPn-insensitive A subunits. Finally, channels formed by mixtures of PIPn-insensitive A3 subunits, having complementary mutations in N- and/or C-terminal regions, restored PIPn regulation, implying that intersubunit N–C interactions help control the phosphoinositide sensitivity of cone CNG channels.
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影响因子：
4.8
作者：
Abderemane-Ali, Fayal;Es-Salah-Lamoureux, Zeineb;Loussouarn, Gildas
通讯作者：
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DOI：
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发表时间：
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期刊：
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影响因子：
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DOI：
10.1074/jbc.m110.214650
发表时间：
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The Journal of biological chemistry
影响因子：
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DOI：
10.1085/jgp.116.6.755
发表时间：
2000-12
期刊：
The Journal of general physiology
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通讯作者：
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