Nav1.7 is phosphorylated by Fyn tyrosine kinase which modulates channel expression and gating in a cell type-dependent manner

被引:12
作者
Li, Yangyang [1 ,2 ]
Zhu, Tengteng [1 ,2 ]
Yang, Huan [1 ,2 ]
Dib-Hajj, Sulayman D. [3 ,4 ]
Waxman, Stephen G. [3 ,4 ]
Yu, Ye [5 ]
Xu, Tian-Le [1 ,2 ]
Cheng, Xiaoyang [1 ,2 ]
机构
[1] Shanghai Jiao Tong Univ, Sch Med, Discipline Neurosci, Inst Med Sci, Shanghai 200025, Peoples R China
[2] Shanghai Jiao Tong Univ, Sch Med, Dept Anat & Physiol, Inst Med Sci, Shanghai 200025, Peoples R China
[3] Yale Univ, Sch Med, Dept Neurol, Ctr Neurosci & Regenerat Res, New Haven, CT 06510 USA
[4] Vet Adm Connecticut Healthcare Syst, Rehabil Res Ctr, West Haven, CT USA
[5] Shanghai Jiao Tong Univ, Inst Med Sci, Dept Pharmacol, Sch Med, Shanghai, Peoples R China
基金
中国国家自然科学基金;
关键词
Voltage-gated sodium channel; Fyn; patch clamp; tyrosine kinase; phosphorylation; NA(V)1.7 SODIUM-CHANNELS; NEURITE OUTGROWTH; NMDA RECEPTOR; INACTIVATION; CONTRIBUTES; NEURONS; RESIDUE; ERK1/2; SRC;
D O I
10.1177/1744806918782229
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Voltage-gated sodium channel Nav1.7 is a key molecule in nociception, and its dysfunction has been associated with various pain disorders. Here, we investigated the regulation of Nav1.7 biophysical properties by Fyn, an Src family tyrosine kinase. Nav1.7 was coexpressed with either constitutively active (Fyn(CA)) or dominant negative (Fyn(DN)) variants of Fyn kinase. Fyn(CA) elevated protein expression and tyrosine phosphorylation of Nav1.7 channels. Site-directed mutagenesis analysis identified two tyrosine residues (Y1470 and Y1471) located within the Nav1.7 DIII-DIV linker (L3) as phosphorylation sites of Fyn. Whole-cell recordings revealed that Fyn(CA) evoked larger changes in Nav1.7 biophysical properties when expressed in ND7/23 cells than in Human Embryonic Kidney (HEK) 293 cells, suggesting a cell type-specific modulation of Nav1.7 by Fyn kinase. In HEK 293 cells, substitution of both tyrosine residues with phenylalanine dramatically reduced current amplitude of mutant channels, which was partially rescued by expressing mutant channels in ND7/23 cells. Phenylalanine substitution showed little effect on Fyn(CA)-induced changes in Nav1.7 activation and inactivation, suggesting additional modifications in the channel or modulation by interaction with extrinsic factor(s). Our study demonstrates that Nav1.7 is a substrate for Fyn kinase, and the effect of the channel phosphorylation depends on the cell background. Fyn-mediated modulation of Nav1.7 may regulate DRG neuron excitability and contribute to pain perception. Whether this interaction could serve as a target for developing new pain therapeutics requires future study.
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页数:14
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