PLCδ1 Plays Central Roles in the Osmotic Activation of ΔN-TRPV1 Channels in Mouse Supraoptic Neurons and in Murine Osmoregulation
PLCδ1 Plays Central Roles in the Osmotic Activation of ΔN-TRPV1 Channels in Mouse Supraoptic Neurons and in Murine Osmoregulation
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DOI：
10.1523/jneurosci.2892-20.2021
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发表时间：
2021-04-21
影响因子：
5.3
通讯作者：
Fisher, Thomas E.
中科院分区：
文献类型：
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作者：
Park, Sung Jin;Haan, Kirk D.;Fisher, Thomas E.
下丘脑的大细胞神经分泌细胞（MNCs）在β-淀粉样蛋白的调节中起着至关重要的作用，但MNCs β-淀粉样蛋白敏感性的机制还不完全清楚。我们以前表明，高渗透压激活磷脂酶C（PLC）在大鼠MNCs中的钙离子依赖性的方式和PLC的激活是必要的充分渗透激活的N-末端变体的TRPV 1（三角洲N-TRPV 1）通道。因此，我们假设PLC的Ca 2+依赖性δ 1亚型有助于δ N-TRPV 1激活，并测试转基因PLC δ 1 KO小鼠中MNC功能是否有缺陷。禁水24小时造成更大的增加，血清渗透压摩尔浓度和体重的损失在PLO% KO小鼠比对照组小鼠。在暴露于高渗溶液之前和之后，使用全细胞膜片钳测量急性分离的小鼠MNCs的动作电位和Δ N-TRPV 1电流。该处理引起从对照小鼠分离的MNC中Delta N-TRPV 1电流的显著激活和放电率的增加，但不引起从PLC Delta 1 KO小鼠分离的MNC中的放电率的增加。膜下丝状肌动蛋白测定分离的MNCs治疗前和治疗后，血管紧张素II和高渗溶液。两种处理均引起从对照小鼠分离的MNC中丝状肌动蛋白荧光的增加，但在PLC delta 1 KO小鼠的MNC中两种反应均显著减弱。我们的数据表明PLC delta 1亚型在Delta N-TRPV 1通道的激活和MNCs的神经感觉转导中起关键作用。这项研究推进了我们对哺乳动物神经调节的分子机制的理解。
The magnocellular neurosecretory cells (MNCs) of the hypothalamus play a vital role in osmoregulation, but the mechanisms underlying MNC osmosensitivity are not fully understood. We showed previously that high osmolality activates phospholipase C (PLC) in rat MNCs in a Ca2+-dependent manner and that PLC activation is necessary for full osmotic activation of an N-terminal variant of the TRPV1 (Delta N-TRPV1) channel. We therefore hypothesized that the Ca2+-dependent delta 1 isoform of PLC contributes to Delta N-TRPV1 activation and tested whether MNC function is defective in a transgenic PLC delta 1 KO mouse. Water deprivation for 24 h caused greater increases in serum osmolality and losses in body weight in PLO% KO mice than it did in control mice. Action potentials and Delta N-TRPV1 currents were measured in acutely isolated mouse MNCs using whole-cell patch clamp before and after exposure to hypertonic solutions. This treatment elicited a significant activation of Delta N-TRPV1 currents and an increase in firing rate in MNCs isolated from control mice, but not from PLC delta 1 KO mice. Submembranous filamentous actin was measured in isolated MNCs before and after treatment with angiotensin II and hypertonic solution. Both treatments caused an increase in filamentous actin fluorescence in MNCs isolated from control mice, but both responses were significantly attenuated in MNCs from PLC delta 1 KO mice. Our data demonstrate that the PLC delta 1 isoform plays a key role in the activation of Delta N-TRPV1 channels and in osmosensory transduction in MNCs. This study advances our understanding of the molecular mechanisms underlying mammalian osmoregulation.