Department of Pharmacology, Hubei University of Science and Technology, 88 Xianning Road, Xianning, Hubei 437100, People's Republic of China.
J Neuroinflammation. 2012 May 29;9:108. doi: 10.1186/1742-2094-9-108.
Prokineticin 2 (PK2) is a secreted protein and causes potent hyperalgesia in vivo, and is therefore considered to be a new pronociceptive mediator. However, the molecular targets responsible for the pronociceptive effects of PK2 are still poorly understood. Here, we have found that PK2 potentiates the activity of acid-sensing ion channels in the primary sensory neurons.
In the present study, experiments were performed on neurons freshly isolated from rat dorsal root ganglion by using whole-cell patch clamp and voltage-clamp recording techniques.
PK2 dose-dependently enhanced proton-gated currents with an EC₅₀ of 0.22 ± 0.06 nM. PK2 shifted the proton concentration-response curve upwards, with a 1.81 ± 0.11 fold increase of the maximal current response. PK2 enhancing effect on proton-gated currents was completely blocked by PK2 receptor antagonist. The potentiation was also abolished by intracellular dialysis of GF109203X, a protein kinase C inhibitor, or FSC-231, a protein interacting with C-kinase 1 inhibitor. Moreover, PK2 enhanced the acid-evoked membrane excitability of rat dorsal root ganglion neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acid stimuli. Finally, PK2 exacerbated nociceptive responses to the injection of acetic acid in rats.
These results suggest that PK2 increases the activity of acid-sensing ion channels via the PK2 receptor and protein kinase C-dependent signal pathways in rat primary sensory neurons. Our findings support that PK2 is a proalgesic factor and its signaling likely contributes to acidosis-evoked pain by sensitizing acid-sensing ion channels.
促动力素 2（PK2）是一种分泌蛋白，在体内引起强烈的痛觉过敏，因此被认为是一种新的伤害感受性介质。然而，导致 PK2 产生伤害感受性作用的分子靶点仍知之甚少。在这里，我们发现 PK2 可增强初级感觉神经元中酸敏离子通道的活性。
本研究采用全细胞膜片钳和电压钳记录技术，在大鼠背根神经节分离的神经元上进行了实验。
PK2 剂量依赖性地增强质子门控电流，EC₅₀为 0.22±0.06 nM。PK2 使质子浓度-反应曲线向上移位，最大电流反应增加 1.81±0.11 倍。PK2 受体拮抗剂完全阻断了 PK2 对质子门控电流的增强作用。PK2 对质子门控电流的增强作用也被蛋白激酶 C 抑制剂 GF109203X 或与 C 激酶 1 相互作用的蛋白抑制剂 FSC-231 细胞内透析所消除。此外，PK2 增强了大鼠背根神经节神经元的酸诱发膜兴奋性，并导致酸刺激引起的去极化幅度和尖峰数量显著增加。最后，PK2 加剧了大鼠注射醋酸引起的疼痛反应。
这些结果表明，PK2 通过 PK2 受体和蛋白激酶 C 依赖性信号通路增加大鼠初级感觉神经元中酸敏离子通道的活性。我们的发现支持 PK2 是一种伤害感受性因子，其信号可能通过敏化酸敏离子通道来促进酸中毒引起的疼痛。
