Enhanced sodium channel inactivation by temperature and FHF2 deficiency blocks heat nociception.
Enhanced sodium channel inactivation by temperature and FHF2 deficiency blocks heat nociception.
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DOI：
10.1097/j.pain.0000000000002822
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发表时间：
2023-06-01
期刊：
影响因子：
7.4
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中科院分区：
文献类型：
--
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热伤害性感受需要FHF2(FGF13)对河豚毒素敏感和河豚毒素抗性钠通道失活门控的调节。瞬时电压门控钠电流对神经元和心肌细胞动作电位的启动和传导是必不可少的。钠电流的幅度和持续时间由与电压门控钠通道(NAV)胞浆尾部相关的细胞内成纤维细胞生长因子同源因子(FHFs/iFGFs)调节，而FHF基因的遗传消融会干扰神经和心脏功能。在已报道的表型中，Fhf2基因缺失的小鼠经历了致命的高温诱导的心脏传导阻滞，这是由于FHF2缺乏和温度升高对心脏钠通道(NaV1.5)失活率的共同影响。Fhf2基因缺失的小鼠也表现出缺乏热伤害感受，同时保留了其他体感能力。在这里，我们使用电生理和计算方法来解释热伤害性缺陷可以通过高温和FHF2缺乏对背根节C纤维中表达的Nav1.7和河豚毒素抗性钠通道的快速失活门控的综合影响来解释。因此，Fhf2基因缺失小鼠的神经和心脏热相关缺陷源于FHF缺陷和温度对不同组织中NAV失活门控动力学的共同影响。
FHF2 (FGF13) modulation of tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channel inactivation gating is required for heat nociception. Transient voltage-gated sodium currents are essential for the initiation and conduction of action potentials in neurons and cardiomyocytes. The amplitude and duration of sodium currents are tuned by intracellular fibroblast growth factor homologous factors (FHFs/iFGFs) that associate with the cytoplasmic tails of voltage-gated sodium channels (Navs), and genetic ablation of Fhf genes disturbs neurological and cardiac functions. Among reported phenotypes, Fhf2null mice undergo lethal hyperthermia-induced cardiac conduction block attributable to the combined effects of FHF2 deficiency and elevated temperature on the cardiac sodium channel (Nav1.5) inactivation rate. Fhf2null mice also display a lack of heat nociception, while retaining other somatosensory capabilities. Here, we use electrophysiological and computational methods to show that the heat nociception deficit can be explained by the combined effects of elevated temperature and FHF2 deficiency on the fast inactivation gating of Nav1.7 and tetrodotoxin-resistant sodium channels expressed in dorsal root ganglion C fibers. Hence, neurological and cardiac heat-associated deficits in Fhf2null mice derive from shared impacts of FHF deficiency and temperature towards Nav inactivation gating kinetics in distinct tissues.
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