Isensee Joerg, Schild Cosimo, Schwede Frank, Hucho Tim
Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology and Pain Research, University Hospital of Cologne, Robert Koch Str. 10, Cologne D-50931, Germany
Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology and Pain Research, University Hospital of Cologne, Robert Koch Str. 10, Cologne D-50931, Germany.
J Cell Sci. 2017 Jul 1;130(13):2134-2146. doi: 10.1242/jcs.197327. Epub 2017 May 17.
Maturation of nociceptive neurons depends on changes in transcription factors, ion channels and neuropeptides. Mature nociceptors initiate pain in part by drastically reducing the activation threshold via intracellular sensitization signaling. Whether sensitization signaling also changes during development and aging remains so far unknown. Using a novel automated microscopy approach, we quantified changes in intracellular signaling protein expression and in their signaling dynamics, as well as changes in intracellular signaling cascade wiring, in sensory neurons from newborn to senescent (24 months of age) rats. We found that nociceptive subgroups defined by the signaling components protein kinase A (PKA)-RIIβ (also known as PRKAR2B) and CaMKIIα (also known as CAMK2A) developed at around postnatal day 10, the time of nociceptor maturation. The integrative nociceptor marker, PKA-RIIβ, allowed subgroup segregation earlier than could be achieved by assessing the classical markers TRPV1 and Na1.8 (also known as SCN10A). Signaling kinetics remained constant over lifetime despite in part strong changes in the expression levels. Strikingly, we found a mechanism important for neuronal memory - i.e. the crosstalk from cAMP and PKA to ERK1 and ERK2 (ERK1/2, also known as MAPK3 and MAPK1, respectively) - to emerge postnatally. Thus, maturation of nociceptors is closely accompanied by altered expression, activation and connectivity of signaling pathways known to be central for pain sensitization and neuronal memory formation.
伤害性神经元的成熟取决于转录因子、离子通道和神经肽的变化。成熟的伤害感受器部分通过细胞内敏化信号大幅降低激活阈值来引发疼痛。到目前为止，尚不清楚敏化信号在发育和衰老过程中是否也会发生变化。我们使用一种新型的自动显微镜方法，对新生至衰老（24月龄）大鼠感觉神经元中的细胞内信号蛋白表达及其信号动力学变化，以及细胞内信号级联连接的变化进行了量化。我们发现，由信号成分蛋白激酶A（PKA）-RIIβ（也称为PRKAR2B）和钙调蛋白激酶IIα（也称为CAMK2A）定义的伤害性亚组在出生后第10天左右发育，这也是伤害感受器成熟的时间。整合性伤害感受器标志物PKA-RIIβ比通过评估经典标志物TRPV1和Na1.8（也称为SCN10A）能更早地实现亚组分离。尽管表达水平部分发生了强烈变化，但信号动力学在整个生命周期中保持不变。令人惊讶的是，我们发现了一种对神经元记忆很重要的机制——即从cAMP和PKA到细胞外调节蛋白激酶1和2（ERK1/2，也分别称为MAPK3和MAPK1）的串扰——在出生后出现。因此，伤害感受器的成熟伴随着已知对疼痛敏化和神经元记忆形成至关重要的信号通路的表达、激活和连接的改变。
