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Depolarization induces nociceptor sensitization by CaV1.2-mediated PKA-II activation
Journal of Cell Biology ( IF 7.4 ) Pub Date : 2021-08-06 , DOI: 10.1083/jcb.202002083
Jörg Isensee 1 , Marianne van Cann 1 , Patrick Despang 2 , Dioneia Araldi 3 , Katharina Moeller 1 , Jonas Petersen 4 , Achim Schmidtko 4 , Jan Matthes 2 , Jon D Levine 3 , Tim Hucho 1
Affiliation  

Depolarization drives neuronal plasticity. However, whether depolarization drives sensitization of peripheral nociceptive neurons remains elusive. By high-content screening (HCS) microscopy, we revealed that depolarization of cultured sensory neurons rapidly activates protein kinase A type II (PKA-II) in nociceptors by calcium influx through CaV1.2 channels. This effect was modulated by calpains but insensitive to inhibitors of cAMP formation, including opioids. In turn, PKA-II phosphorylated Ser1928 in the distal C terminus of CaV1.2, thereby increasing channel gating, whereas dephosphorylation of Ser1928 involved the phosphatase calcineurin. Patch-clamp and behavioral experiments confirmed that depolarization leads to calcium- and PKA-dependent sensitization of calcium currents ex vivo and local peripheral hyperalgesia in the skin in vivo. Our data suggest a local activity-driven feed-forward mechanism that selectively translates strong depolarization into further activity and thereby facilitates hypersensitivity of nociceptor terminals by a mechanism inaccessible to opioids.

中文翻译:

去极化通过 CaV1.2 介导的 PKA-II 激活诱导伤害感受器敏化

去极化驱动神经元可塑性。然而,去极化是否会驱动外周伤害性神经元的敏化仍不清楚。通过高内涵筛选 (HCS) 显微镜,我们发现培养的感觉神经元的去极化通过 CaV1.2 通道的钙流入快速激活伤害感受器中的蛋白激酶 A II 型 (PKA-II)。这种作用受钙蛋白酶调节,但对 cAMP 形成抑制剂(包括阿片类药物)不敏感。反过来,PKA-II 磷酸化 CaV1.2 远端 C 末端的 Ser1928,从而增加通道门控,而 Ser1928 的去磷酸化则涉及磷酸酶钙调神经磷酸酶。膜片钳和行为实验证实,去极化导致离体钙电流的钙和PKA依赖性敏化和体内皮肤局部外周痛觉过敏。我们的数据表明,局部活动驱动的前馈机制可以选择性地将强去极化转化为进一步的活动,从而通过阿片类药物无法达到的机制促进伤害感受器末端的超敏反应。
更新日期:2021-08-06
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