牛津大学David L. Bennett小组宣布他们的研究发现SLC45A4是一种疼痛基因，编码神经元多胺转运蛋白。该项研究成果发表在2025年8月20日出版的《自然》上。

课题组研究人员在英国生物银行（UKB）进行了一项慢性疼痛强度的全基因组关联研究（GWAS），发现疼痛强度与SLC45A4基因位点的变异之间存在显著关联。在母母神经系统中，SLC45A4在背根神经节内的所有感觉神经元亚型中表达丰富，包括伤害感受器。基于细胞的实验表明，SLC45A4是一种选择性质膜多胺转运蛋白，其低温电镜（cryo-EM）结构揭示了多胺识别的调控域和基础。缺乏SLC45A4的小鼠表现出正常的机械敏感性，但对氧、热、氧原诱导的强直性疼痛的敏感性降低，这与C-多模伤害感受器的兴奋性降低有关。因此，他们的发现确立了神经元多胺转运在疼痛感知中的作用，并确定了疼痛治疗干预的靶点。

据介绍，多胺是调节代谢产物，在转录、翻译、细胞信号传导和自噬中起关键作用。它们与多种神经系统疾病有关，包括中风、癫痫和神经变性，并可通过与离子通道的相互作用调节神经元的兴奋性。多胺与疼痛有关，在人类持续疼痛状态和动物疼痛行为的调节中显示出不同的水平。然而，在神经系统中控制多胺运输的系统仍不清楚。

附：英文原文

Title: SLC45A4 is a pain gene encoding a neuronal polyamine transporter

Author: Middleton, Steven J., Marksson, Sigurbjrn, kerlund, Mikael, Deme, Justin C., Tseng, Mandy, Li, Wenqianglong, Zuberi, Sana R., Kuteyi, Gabriel, Sarkies, Peter, Baskozos, Georgios, Perez-Sanchez, Jimena, Farah, Adham, Hbert, Harry L., Toikumo, Sylvanus, Yu, Zhanru, Maxwell, Susan, Dong, Yin Y., Kessler, Benedikt M., Kranzler, Henry R., Linley, John E., Smith, Blair H., Lea, Susan M., Parker, Joanne L., Lyssenko, Valeriya, Newstead, Simon, Bennett, David L.

Issue&Volume: 2025-08-20

Abstract: Polyamines are regulatory metabolites with key roles in transcription, translation, cell signalling and autophagy1. They are implicated in multiple neurological disorders, including stroke, epilepsy and neurodegeneration, and can regulate neuronal excitability through interactions with ion channels2. Polyamines have been linked to pain, showing altered levels in human persistent pain states and modulation of pain behaviour in animal models3. However, the systems governing polyamine transport within the nervous system remain unclear. Here, undertaking a genome-wide association study (GWAS) of chronic pain intensity in the UK Biobank (UKB), we found a significant association between pain intensity and variants mapping to the SLC45A4 gene locus. In the mouse nervous system, Slc45a4 expression is enriched in all sensory neuron subtypes within the dorsal root ganglion, including nociceptors. Cell-based assays show that SLC45A4 is a selective plasma membrane polyamine transporter, and the cryo-electron microscopy (cryo-EM) structure reveals a regulatory domain and basis for polyamine recognition. Mice lacking SLC45A4 show normal mechanosensitivity but reduced sensitivity to noxious heat- and algogen-induced tonic pain that is associated with reduced excitability of C-polymodal nociceptors. Our findings therefore establish a role for neuronal polyamine transport in pain perception and identify a target for therapeutic intervention in pain treatment.

DOI: 10.1038/s41586-025-09326-y

Source: https://www.nature.com/articles/s41586-025-09326-y