Fibroblast growth factor homologous factor 13 regulates Na+ channels and conduction velocity in murine hearts.
Fibroblast growth factor homologous factor 13 regulates Na+ channels and conduction velocity in murine hearts.
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DOI：
10.1161/circresaha.111.247957
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发表时间：
2011-09-16
影响因子：
20.1
通讯作者：
Pitt GS
中科院分区：
文献类型：
--
作者：
Wang C;Hennessey JA;Kirkton RD;Wang C;Graham V;Puranam RS;Rosenberg PB;Bursac N;Pitt GS
成纤维细胞生长因子同源因子（FHF）是成纤维细胞生长因子（FGF）的一个亚家族，不能作为生长因子发挥作用，是Na+通道的细胞内调节剂，并且与神经退行性疾病有关。虽然在胚胎心脏中发现了某些FHF，但在成人心脏中尚未报道，并且尚未显示它们调节内源性心脏Na+通道或参与心脏病理生理学。我们测试了FHF是否调节小鼠心脏中的Na+通道。我们证明了FGF13的亚型是成年小鼠心室肌细胞中的主要FHF。FGF 13直接结合至成年小鼠心室肌细胞的肌膜中的Na 1.5Na + V通道并与其共定位。成年小鼠心室肌细胞中FGF13的敲低揭示了NaV1.5的功能丧失：Na+电流（INa）密度降低，Na+通道可用性降低，并减缓了INa从失活中的恢复。细胞表面生物素化实验显示，在FGF13敲低后，肌膜处的NaV1.5蛋白减少约45%，而未观察到全细胞NaV1.5蛋白或mRNA水平的变化。光学成像在新生大鼠心室肌细胞单层表现出缓慢的传导速度和FGF13敲低后降低的最大捕获率。这些发现表明，FHF是成人心室肌细胞Na+通道的有效调节剂，并表明FHF中的功能丧失突变可能是由NaV1.5功能丧失突变引起的一组类似心律失常和心肌病的基础。
Fibroblast growth factor homologous factors (FHFs), a subfamily of fibroblast growth factors (FGFs) that are incapable of functioning as growth factors, are intracellular modulators of Na+ channels and have been linked to neurodegenerative diseases. Although certain FHFs have been found in embryonic heart, they have not been reported in adult heart, and they have not been shown to regulate endogenous cardiac Na+ channels nor participate in cardiac pathophysiology. We tested whether FHFs regulate Na+ channels in murine heart. We demonstrated that isoforms of FGF13 are the predominant FHFs in adult mouse ventricular myocytes. FGF13 binds directly to, and co-localizes with the Na 1.5 Na+ V channel in the sarcolemma of adult mouse ventricular myocytes. Knockdown of FGF13 in adult mouse ventricular myocytes revealed a loss-of-function of NaV1.5: reduced Na+ current (INa) density, decreased Na+ channel availability, and slowed INa recovery from inactivation. Cell surface biotinylation experiments showed a ~45% reduction in NaV1.5 protein at the sarcolemma after FGF13 knockdown, whereas no changes in whole-cell NaV1.5 protein nor mRNA level were observed. Optical imaging in neonatal rat ventricular myocyte monolayers demonstrated slowed conduction velocity and a reduced maximum capture rate after FGF13 knockdown. These findings show that FHFs are potent regulators of Na+ channels in adult ventricular myocytes and suggest that loss-of-function mutations in FHFs may underlie a similar set of cardiac arrhythmias and cardiomyopathies that result from NaV1.5 loss-of-function mutations.