pThe T-type Casup2+/sup channel Casubv/sub3.2 is expressed in nociceptive and mechanosensitive sensory neurons. The mechanosensitive D-hair (down-hair) neurons, which innervate hair follicles, are characterized by a large-amplitude Casubv/sub3.2 T-current involved in the amplification of slow-moving stimuli. The molecules and signalling pathways that regulate T-current expression in mechanoreceptors are unknown. In the present study, we investigated the effects of NT-4 (neurotrophin-4) on Casubv/sub3.2 T-current expression in D-hair neurons iin vitro/i. Interruption of the supply of NT-4 with peripheral nerve axotomy induced a non-transcriptional decrease in the T-current amplitude of fluorogold-labelled axotomized sensory neurons. The T-current amplitude was restored by incubation with NT-4. Deletion of NT-4 through genetic ablation resulted in a similar selective loss of the large-amplitude T-current in NT-4sup?/?/sup sensory neurons, which was rescued by the addition of NT-4. NT-4 had no effect on the T-current in Casubv/sub3.2sup?/?/sup D-hair neurons. Neither the biophysical properties of the T-current nor the transcript expression of Casubv/sub3.2 were modified by NT-4. Pharmacological screening of signalling pathways activated under the high-affinity NT-4 receptor TrkB (tropomyosin receptor kinase B) identified a role for PI3K (phosphoinositide 3-kinase) in the potentiation of T-current. The results of the present study demonstrate the post-transcriptional up-regulation of the Casubv/sub3.2 T-current through TrkB activation and identify NT-4 as a target-derived factor that regulates the mechanosensitive function of D-hair neurons through expression of the T-current./p
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机译:> T型Ca 2 + sup>通道Ca v sub> 3.2在伤害性和机械敏感的感觉神经元中表达。支配毛囊的机械敏感的D毛(下毛)神经元的特征是参与慢速刺激放大的Ca v sub> 3.2 T电流出现大幅度变化。调节机械感受器中T电流表达的分子和信号通路尚不清楚。在本研究中,我们研究了NT-4(神经营养蛋白4)对D毛神经元体外 i>的Ca v sub> 3.2 T电流表达的影响。 NT-4的供应与周围神经轴突切断术的中断导致荧光金标记的轴突化感觉神经元的T电流幅度的非转录降低。通过与NT-4一起温育来恢复T电流幅度。通过遗传消融删除NT-4导致NT-4 ?/? sup>感觉神经元中大幅度T电流的类似选择性丢失,通过添加NT-4得以挽救。 NT-4对Ca v sub> 3.2 ?/? sup> D-毛神经元的T电流没有影响。 NT-4既没有修饰T电流的生物物理特性,也没有修饰Ca v sub> 3.2的转录本表达。在高亲和力NT-4受体TrkB(原肌球蛋白受体激酶B)下激活的信号通路的药理学筛选确定了PI3K(磷酸肌醇3激酶)在T电流增强中的作用。本研究的结果证明了通过TrkB激活后Ca v sub> 3.2 T电流的转录后上调,并确定NT-4是调控D的机械敏感性功能的靶标衍生因子。毛神经元通过T电流的表达。 p>
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