Foulkes Thomas, Nassar Mohammed A, Lane Tim, Matthews Elizabeth A, Baker Mark D, Gerke Volker, Okuse Kenji, Dickenson Anthony H, Wood John N
Molecular Nociception Group, Department of Biology, University College London, London WC1E 6BT, United Kingdom.
J Neurosci. 2006 Oct 11;26(41):10499-507. doi: 10.1523/JNEUROSCI.1997-06.2006.
The S100 family protein p11 (S100A10, annexin 2 light chain) is involved in the trafficking of the voltage-gated sodium channel Na(V)1.8, TWIK-related acid-sensitive K+ channel (TASK-1), the ligand-gated ion channels acid-sensing ion channel 1a (ASIC1a) and transient receptor potential vanilloid 5/6 (TRPV5/V6), as well as 5-hydroxytryptamine receptor 1B (5-HT1B), a G-protein-coupled receptor. To evaluate the role of p11 in peripheral pain pathways, we generated a loxP-flanked (floxed) p11 mouse and used the Cre-loxP recombinase system to delete p11 exclusively from nociceptive primary sensory neurons in mice. p11-null neurons showed deficits in the expression of Na(V)1.8, but not of annexin 2. Damage-sensing primary neurons from these animals show a reduced tetrodotoxin-resistant sodium current density, consistent with a loss of membrane-associated Na(V)1.8. Noxious coding in wide-dynamic-range neurons in the dorsal horn was markedly compromised. Acute pain behavior was attenuated in certain models, but no deficits in inflammatory pain were observed. A significant deficit in neuropathic pain behavior was also apparent in the conditional-null mice. These results confirm an important role for p11 in nociceptor function.
S100家族蛋白p11（S100A10，膜联蛋白2轻链）参与电压门控钠通道Na(V)1.8、TWIK相关酸敏感钾通道（TASK-1）、配体门控离子通道酸敏感离子通道1a（ASIC1a）和瞬时受体电位香草酸亚型5/6（TRPV5/V6）以及G蛋白偶联受体5-羟色胺受体1B（5-HT1B）的转运。为了评估p11在外周痛觉传导通路中的作用，我们构建了一个loxP侧翼（floxed）的p11小鼠，并使用Cre-loxP重组酶系统专门从小鼠伤害性初级感觉神经元中删除p11。p11基因敲除的神经元显示Na(V)1.8的表达存在缺陷，但膜联蛋白2的表达没有缺陷。来自这些动物的损伤感受性初级神经元显示河豚毒素抗性钠电流密度降低，这与膜相关Na(V)1.8的缺失一致。背角宽动态范围神经元中的伤害性编码明显受损。在某些模型中急性疼痛行为减弱，但未观察到炎症性疼痛缺陷。条件性基因敲除小鼠的神经性疼痛行为也存在明显缺陷。这些结果证实了p11在伤害感受器功能中的重要作用。
