Department of Neurosciences, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
Solomon H. Snyder Department of Neuroscience and Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Neuron. 2022 Jul 20;110(14):2315-2333.e6. doi: 10.1016/j.neuron.2022.04.021. Epub 2022 May 12.
Heat perception enables acute avoidance responses to prevent tissue damage and maintain body thermal homeostasis. Unlike other modalities, how heat signals are processed in the spinal cord remains unclear. By single-cell gene profiling, we identified ErbB4, a transmembrane tyrosine kinase, as a novel marker of heat-sensitive spinal neurons in mice. Ablating spinal ErbB4+ neurons attenuates heat sensation. These neurons receive monosynaptic inputs from TRPV1+ nociceptors and form excitatory synapses onto target neurons. Activation of ErbB4+ neurons enhances the heat response, while inhibition reduces the heat response. We showed that heat sensation is regulated by NRG1, an activator of ErbB4, and it involves dynamic activity of the tyrosine kinase that promotes glutamatergic transmission. Evidence indicates that the NRG1-ErbB4 signaling is also engaged in hypersensitivity of pathological pain. Together, these results identify a spinal neuron connection consisting of ErbB4+ neurons for heat sensation and reveal a regulatory mechanism by the NRG1-ErbB4 signaling.
热感觉使急性回避反应能够防止组织损伤并维持身体热平衡。与其他模态不同，热信号在脊髓中是如何被处理的仍不清楚。通过单细胞基因分析，我们在小鼠中鉴定出 ErbB4，一种跨膜酪氨酸激酶，作为热敏性脊髓神经元的新型标志物。消融脊髓 ErbB4+神经元可减弱热感觉。这些神经元从 TRPV1+伤害感受器接收单突触输入，并形成兴奋性突触到靶神经元。ErbB4+神经元的激活增强了热反应，而抑制则降低了热反应。我们表明，热感觉受 ErbB4 激活物 NRG1 的调节，涉及促进谷氨酸能传递的酪氨酸激酶的动态活性。有证据表明，NRG1-ErbB4 信号也参与病理性疼痛的过敏。总之，这些结果确定了由 ErbB4+神经元组成的用于热感觉的脊髓神经元连接，并揭示了 NRG1-ErbB4 信号的调节机制。
