The auxiliary subunits Neto1 and Neto2 reduce voltage-dependent inhibition of recombinant kainate receptors.
The auxiliary subunits Neto1 and Neto2 reduce voltage-dependent inhibition of recombinant kainate receptors.
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DOI：
10.1523/jneurosci.2211-12.2012
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发表时间：
2012-09-12
期刊：
影响因子：
--
通讯作者：
Mott DD
中科院分区：
文献类型：
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作者：
Fisher JL;Mott DD
红藻氨酸受体可以受到细胞内多胺的电压依赖性阻断，从而导致电流-电压关系的向内整流。对多胺阻断的敏感性在很大程度上取决于孔结构域内可以通过RNA编辑改变的残基的身份。这个过程导致编码的谷氨酰胺（Q）被带正电荷的精氨酸（R）取代，消除了多胺抑制，从而消除了内向整流。在神经元中，红藻氨酸受体可以与辅助亚基Neto 1或Neto 2结合。这些跨膜蛋白以亚基依赖性方式改变受体的运输、通道动力学和药理学。我们发现，Neto亚基与重组GluK 2（Q）红藻氨酸受体的共表达大大减少了内向整流，而不改变钙渗透性。这种作用与通道动力学的调节是分开的，因为Neto蛋白的细胞外LDLa结构域内的突变完全消除了它们对脱敏的作用，但仅降低了它们对整流的作用。相反，删除细胞内的C-末端结构域的Neto 1或Neto 2或中和带正电荷的残基在这个域内防止整流减少，但不改变对通道动力学的影响。这些结果表明Neto 1和Neto 2在调节红藻氨酸受体功能中的新作用，并确定了这些辅助亚基中对介导其作用重要的结构域。
Kainate receptors can be subject to voltage-dependent block by intracellular polyamines, which causes inward rectification of the current-voltage relationship. Sensitivity to polyamine block is largely determined by the identity of a residue within the pore domain that can be altered through RNA editing. This process causes replacement of the encoded glutamine(Q) with a positively charged arginine(R), eliminating polyamine inhibition and thus inward rectification. In neurons, kainate receptors can associate with the auxiliary subunits Neto1 or Neto2. These transmembrane proteins alter the trafficking, channel kinetics, and pharmacology of the receptors in a subunit-dependent manner. We found that co-expression of Neto subunits with recombinant GluK2(Q) kainate receptors greatly reduced inward rectification, without altering calcium permeability. This effect was separate from modulation of channel kinetics, as mutations within the extracellular LDLa domain of the Neto proteins completely eliminated their effects on desensitization but only reduced their effects on rectification. Conversely, deletion of the intracellular C-terminal domain of Neto1 or Neto2 or neutralization of positively charged residues within this domain prevented the reduction in rectification, but did not alter effects on channel kinetics. These results demonstrate new roles for Neto1 and Neto2 in regulating kainate receptor function and identify domains within these auxiliary subunits important for mediating their effects.