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首页> 外文期刊>The European Journal of Neuroscience >Canonical transient receptor potential channel subtype 3-mediated hair cell Ca2+ entry regulates sound transduction and auditory neurotransmission
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Canonical transient receptor potential channel subtype 3-mediated hair cell Ca2+ entry regulates sound transduction and auditory neurotransmission

机译：典范的瞬态受体电位通道亚型3介导的毛细胞Ca2 +进入调节声音的传导和听觉神经传递。

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摘要

The physiological significance of canonical transient receptor potential (TRPC) ion channels in sensory systems is rapidly emerging. Heterologous expression studies show that TRPC3 is a significant Ca2+ entry pathway, with dual activation via G protein-coupled receptor (GPCR)-phospholipase C-diacylglycerol second messenger signaling, and through negative feedback, whereby a fall in cytosolic Ca2+ releases Ca2+-calmodulin channel block. We hypothesised that the latter process contributes to cochlear hair cell cytosolic Ca2+ homeostasis. Confocal microfluorimetry with the Ca2+ indicator Fluo-4 acetoxymethylester showed that, when cytosolic Ca2+ was depleted, Ca2+ re-entry was significantly impaired in mature TRPC3-/- inner and outer hair cells. The impact of this disrupted Ca2+ homeostasis on sound transduction was assessed with the use of distortion product otoacoustic emissions (DPOAEs), which constitute a direct measure of the outer hair cell transduction that underlies hearing sensitivity and frequency selectivity. TRPC3-/- mice showed significantly stronger DPOAE (2f1 - f2) growth functions than wild-type (WT) littermates within the frequency range of best hearing acuity. This translated to hyperacusis (decreased threshold) measured by the auditory brainstem response (ABR). TRPC3-/- and WT mice did not differ in the levels of temporary and permanent threshold shift arising from noise exposure, indicating that potential GPCR signaling via TRPC3 is not pronounced. Overall, these data suggest that the Ca2+ set-point in the hair cell, and hence membrane conductance, is modulated by TRPC3s through their function as a negative feedback-regulated Ca2+ entry pathway. This TPRC3-regulated Ca2+ homeostasis shapes the sound transduction input-output function and auditory neurotransmission. Ca2+ microfluorimetry indicated that cochlear hair cells lacking the TRPC3 ion channel subunit had significantly reduced Ca2+ entry to balance cytosolic Ca2+ depletion via PMCA2a Ca2+ pumps. Thus hair cell cytosolic Ca2+ homeostasis was disrupted, likely affecting membrane conductance and sound transduction. This postulate was supported by enhanced hearing sensitivity (hyperacusis) in the TRPC3 knockout mice, determined by auditory brainstem response and distortion product otoacoustic emission.
机译：感觉系统中规范瞬态受体电位（TRPC）离子通道的生理意义正在迅速显现。异源表达研究表明，TRPC3是一条重要的Ca2 +进入途径，通过G蛋白偶联受体（GPCR）-磷脂酶C-二甘油甘油第二信使信号传导并通过负反馈双重激活，从而使胞质Ca2 +下降释放Ca2 +-钙调蛋白通道块。我们假设，后者的过程有助于耳蜗毛细胞的胞质Ca2 +稳态。与Ca2 +指示剂Fluo-4乙酰氧基甲基酯的共聚焦微荧光分析表明，当胞浆中的Ca2 +耗尽时，成熟的TRPC3-/-内部和外部毛细胞中的Ca2 +再进入受到显着损害。通过使用失真产物耳声发射（DPOAEs）评估了这种破坏的Ca2 +稳态对声音传导的影响，该声音产物构成了外部毛细胞传导的直接量度，是听力敏感性和频率选择性的基础。在最佳听觉敏锐度的频率范围内，TRPC3-/-小鼠的DPOAE（2f1-f2）生长功能明显强于野生型（WT）同窝仔。这转换为听觉脑干反应（ABR）测得的听觉亢进（阈值降低）。 TRPC3-/-和WT小鼠在噪声暴露引起的暂时性和永久性阈值漂移水平上没有差异，这表明未通过TRPC3发出潜在的GPCR信号。总体而言，这些数据表明，毛发细胞中的Ca2 +设定点和因此的膜电导受TRPC3通过其作为负反馈调节的Ca2 +进入途径的作用而被调节。 TPRC3调节的Ca2 +稳态调节了声音转导的输入输出功能和听觉神经传递。 Ca2 +荧光法表明，缺少TRPC3离子通道亚基的耳蜗毛细胞已显着减少了Ca2 +的进入，从而通过PMCA2a Ca2 +泵平衡了胞质Ca2 +的消耗。因此，毛细胞的胞质Ca2 +稳态被破坏，可能影响膜电导和声音传导。通过听觉脑干反应和畸变产物耳声发射确定的TRPC3基因敲除小鼠的听觉敏感性（hyperacusis）增强支持了这一假设。

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