Department of Biological Sciences, Hunter College of City University, New York, NY, United States.
Program in Biology, Graduate Center of City University, New York, NY, United States.
Pain. 2023 Jun 1;164(6):1321-1331. doi: 10.1097/j.pain.0000000000002822. Epub 2022 Nov 9.
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 (Na v s), 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 (Na v 1.5) 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 Na v 1.7 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 Na v inactivation gating kinetics in distinct tissues.
瞬时电压门控钠电流对于神经元和心肌细胞动作电位的产生和传导至关重要。钠离子电流的幅度和持续时间由与电压门控钠通道（Na v s）细胞质尾部结合的细胞内成纤维细胞生长因子同源因子（FHFs/iFGFs）调节，而 Fhf 基因的缺失会扰乱神经和心脏功能。在已报道的表型中，Fhf2null 小鼠发生致命性高热诱导的心脏传导阻滞，归因于 FHF2 缺乏和高温对心脏钠通道（Na v 1.5）失活速率的综合影响。Fhf2null 小鼠还表现出缺乏热痛觉，同时保留其他躯体感觉能力。在这里，我们使用电生理和计算方法表明，热痛觉缺失可以通过高温和 FHF2 缺乏对背根神经节 C 纤维中表达的 Na v 1.7 和河豚毒素抗性钠通道的快速失活门控的综合作用来解释。因此，Fhf2null 小鼠的神经和心脏与热相关的缺陷源于 FHF 缺乏和温度对不同组织中 Na v 失活门控动力学的共同影响。
