Most mammalian neurons have a resting membrane potential (RMP) of ~ -50 mV to -70 mV, significantly above the equilibrium potential of K+ (EK) of ~ -90 mV. The resting Na+-leak conductance is a major mechanism by which neurons maintain their RMPs above EK. In the hippocampal neurons, the TTX-insensitive, voltage-independent Na+ leak is mediated by the NALCN cation channel. Extracellular Ca2+ also controls the sizes of NALCN current (INALCN) in a G-protein-dependent fashion. The molecular identities of the basal Na+ conductances and their regulation in other regions in the central nervous system and in the peripheral nervous system are less established. Here we show that neurons cultured from mouse cortices, ventral tegmental area, spinal cord and dorsal root ganglia all have a NALCN-dependent basal Na+-leak conductance that is absent in NALCN knockout mice. Like in hippocampal neurons, a decrease in [Ca2+]e increases INALCN. Using shRNA knockdown, we show that the regulation of INALCN by extracellular Ca2+ in neurons requires the Ca2+-sensing G-protein-coupled receptor CaSR. Surprisingly, the functional coupling from [Ca2+]e to NALCN requires CaSR's distal C-terminal domain that is dispensable for the receptor's ability to couple [Ca2+]e to its canonical signaling targets such as PLC and MAPK. In addition, several epilepsy-associated human CaSR mutations, though sparing the receptor's ability to sense Ca2+e to maintain systemic [Ca2+], disrupt the ability of CaSR to regulate NALCN. These findings uncover a unique mechanism by which CaSR regulates neuronal excitability via NALCN in the central and peripheral nervous system.

中文翻译：

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钙敏感受体的癫痫相关突变破坏神经元细胞外钙对NALCN钠泄漏通道的调节。

大多数哺乳动物神经元的静息膜电位（RMP）约为-50 mV至-70 mV，大大高于K +的平衡电位（EK）约为-90 mV。静息的Na +泄漏电导是神经元将其RMP维持在EK以上的主要机制。在海马神经元中，TTCN不敏感，电压独立的Na +泄漏是由NALCN阳离子通道介导的。细胞外Ca2 +也以G蛋白依赖性方式控制NALCN电流（INALCN）的大小。在中枢神经系统和周围神经系统的其他区域中，基础Na +电导的分子身份及其调控尚不明确。在这里，我们显示了从小鼠皮质，腹侧被盖区培养的神经元，脊髓和背根神经节均具有NALCN依赖的基础Na +泄漏电导，而在NALCN剔除小鼠中则不存在。像在海马神经元中一样，[Ca2 +] e的减少会增加INALCN。使用shRNA敲低，我们表明神经元中胞外Ca2 +对INALCN的调节需要Ca2 +感应G蛋白偶联受体CaSR。出乎意料的是，从[Ca2 +] e到NALCN的功能偶联需要CaSR的远端C末端结构域，这对于受体将[Ca2 +] e与其经典信号传导靶标（例如PLC和MAPK）偶联的能力而言是必不可少的。此外，一些癫痫相关的人类CaSR突变，尽管不影响受体感知Ca2 + e维持系统性[Ca2 +]的能力，却破坏了CaSR调节NALCN的能力。