Nav1.3 and FGF14 are primary determinants of the TTX-sensitive sodium current in mouse adrenal chromaffin cells.
Nav1.3 and FGF14 are primary determinants of the TTX-sensitive sodium current in mouse adrenal chromaffin cells.
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DOI：
10.1085/jgp.202012785
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发表时间：
2021-04-05
期刊：
影响因子：
--
通讯作者：
Lingle CJ
中科院分区：
文献类型：
--
作者：
Martinez-Espinosa PL;Yang C;Xia XM;Lingle CJ
马丁内斯-埃斯皮诺萨等人。结果表明，FGF14和电压依赖的Na+通道Nav1.3是小鼠肾上腺嗜铬细胞快速失活电流和NAV通道可用性的主要调节因子。他们的结果揭示了FGF14在调节NAV通道功能中的作用。啮齿动物的肾上腺嗜铬细胞(CCS)表达迅速失活的河豚毒素(TTX)敏感的钠通道。由此产生的海流通常被归因于Nav1.7，尽管也有人提出Nav1.3可能起到了作用。大鼠CCS中的NAV通道通过两条独立的途径迅速失活，这两条途径的恢复时间不同。一个亚群的恢复时间常数类似于传统的快速失活，而另一个∼亚群的恢复速度要慢10倍，但这两个通路都可以在单一的同质通道群中发挥作用。在这里，我们使用Nav1.3 KO小鼠来探索CCS中NAV电流的性质和分子组成。我们发现，在被检测的大约一半的CCS中，NA1.3的缺失消除了所有的NAV电流，而在其余的CCS中仍然观察到了少量的快速失活的NAV电流。为了探索从失活中缓慢恢复的可能分子成分，我们使用了小鼠成纤维细胞生长因子同源因子14(FGF14)的空基因。在这些细胞中，从快速失活中恢复的慢成分在大多数CC中完全不存在，快速恢复的时间常数没有变化。在FGF14 KO小鼠中，WT细胞在刺激序列期间NAV电流减少的使用依赖性被完全取消，直接证明了从失活中缓慢恢复在确定NAV电流可用性方面的作用。我们的结果表明，FGF14介导的失活是定义CCS中NAV可用性随使用而变化的主要决定因素。这些结果表明，与其他NAV亚型一样，Nav1.3也可以与成纤维细胞生长因子亚基配对，强烈调节NAV通道功能。
Martinez-Espinosa et al. show that FGF14 and the voltage-dependent Na+ channel Nav1.3 are the main regulators of rapidly inactivating currents and Nav channel availability in mouse adrenal chromaffin cells. Their results uncover a role for FGF14 in regulating Nav channel function. Adrenal chromaffin cells (CCs) in rodents express rapidly inactivating, tetrodotoxin (TTX)-sensitive sodium channels. The resulting current has generally been attributed to Nav1.7, although a possible role for Nav1.3 has also been suggested. Nav channels in rat CCs rapidly inactivate via two independent pathways which differ in their time course of recovery. One subpopulation recovers with time constants similar to traditional fast inactivation and the other ∼10-fold slower, but both pathways can act within a single homogenous population of channels. Here, we use Nav1.3 KO mice to probe the properties and molecular components of Nav current in CCs. We find that the absence of Nav1.3 abolishes all Nav current in about half of CCs examined, while a small, fast inactivating Nav current is still observed in the rest. To probe possible molecular components underlying slow recovery from inactivation, we used mice null for fibroblast growth factor homology factor 14 (FGF14). In these cells, the slow component of recovery from fast inactivation is completely absent in most CCs, with no change in the time constant of fast recovery. The use dependence of Nav current reduction during trains of stimuli in WT cells is completely abolished in FGF14 KO mice, directly demonstrating a role for slow recovery from inactivation in determining Nav current availability. Our results indicate that FGF14-mediated inactivation is the major determinant defining use-dependent changes in Nav availability in CCs. These results establish that Nav1.3, like other Nav isoforms, can also partner with FGF subunits, strongly regulating Nav channel function.
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