Department of Pharmacology, Physiology and Neuroscience, Rutgers, New Jersey Medical School, Newark, NJ, USA.
Department of Physiology, Gyeongsang National University Medical School, Jinju, Korea.
Nat Commun. 2023 Sep 21;14(1):5883. doi: 10.1038/s41467-023-41577-z.
Long-chain acyl-coenzyme A (LC-CoA) is a crucial metabolic intermediate that plays important cellular regulatory roles, including activation and inhibition of ion channels. The structural basis of ion channel regulation by LC-CoA is not known. Transient receptor potential vanilloid 5 and 6 (TRPV5 and TRPV6) are epithelial calcium-selective ion channels. Here, we demonstrate that LC-CoA activates TRPV5 and TRPV6 in inside-out patches, and both exogenously supplied and endogenously produced LC-CoA can substitute for the natural ligand phosphatidylinositol 4,5-bisphosphate (PI(4,5)P) in maintaining channel activity in intact cells. Utilizing cryo-electron microscopy, we determined the structure of LC-CoA-bound TRPV5, revealing an open configuration with LC-CoA occupying the same binding site as PI(4,5)P in previous studies. This is consistent with our finding that PI(4,5)P could not further activate the channels in the presence of LC-CoA. Our data provide molecular insights into ion channel regulation by a metabolic signaling molecule.
长链酰基辅酶 A（LC-CoA）是一种重要的代谢中间产物，在细胞调节中发挥着重要作用，包括离子通道的激活和抑制。LC-CoA 调节离子通道的结构基础尚不清楚。瞬时受体电位香草酸 5 和 6（TRPV5 和 TRPV6）是上皮细胞钙选择性离子通道。本文中，我们证明 LC-CoA 在膜片钳外翻模式下激活 TRPV5 和 TRPV6，并且外源性和内源性 LC-CoA 均可替代天然配体磷脂酰肌醇 4,5-二磷酸（PI（4,5）P），在完整细胞中维持通道活性。我们利用冷冻电镜确定了 LC-CoA 结合 TRPV5 的结构，揭示了 LC-CoA 与之前研究中 PI（4,5）P 占据相同结合位点的开放构象。这与我们的发现一致，即在 LC-CoA 存在的情况下，PI（4,5）P 不能进一步激活通道。我们的数据为代谢信号分子调节离子通道提供了分子见解。
