The spinal calcium sensor STIM1 is an excitatory neuronal marker involving in the development of neuropathic pain

Huijuan Hu1,2, Jingsheng Xia1, Yixiao Mei1,2, Dongyu Wei2, Yannong Dou1, Renee Jean-Toussaint1, Ruby Gao1, Yuang-Xiang Tao2, Alex Bekker2 

 

1Department of Anesthesiology, Rutgers New Jersey Medical School, Newark; 2Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia. 

It is well known that calcium mediates a remarkable variety of cellular functions in neurons and calcium signaling is crucial for the induction of synaptic plasticity, which contributes to the generation and the maintenance of pain hypersensitivity. Calcium-permeable ion channels are the major source and have emerged as targets for chronic pain. Increasing evidence indicates that store-operated calcium channels (SOCs) in the nervous system contribute to neuronal Ca2+ signaling. STIM1, an ER Ca2+ sensor, is a key component of SOCs in spinal cord dorsal horn neurons. However, its expression and functional significance in dorsal horn neurons remain elusive. Here we demonstrate that STIM1 is highly expressed in the superficial dorsal horn and specifically in excitatory dorsal horn neurons. Depletion of calcium store from the endoplasmic reticulum (ER) induces a large calcium entry, which is blocked by a STIM1 inhibitor. Intrathecal injection of a STIM1 inhibitor or conditional deletion of STIM1 in excitatory neurons attenuates spinal nerve injury (SNI)-induced mechanical and thermal hypersensitivity in earlier time points. Our results also show that STIM1 protein level is significantly increased, and the SOC function is enhanced in dorsal horn neurons from SNI mice. To understand how STIM1 contributes to the development of SNI-induced neuropathic pain, we recorded field excitatory postsynaptic potentials (fEPSPs) evoked by dorsal root high-frequency stimulation in the superficial dorsal horn from wild type (WT) and STIM1 KO mice. LTP is dramatically attenuated in the dorsal horn from STIM1 KO mice, suggesting STIM1 is involved in synaptic transmission. Furthermore, we found that AMPA-induced Ca2+ influx is reduced in STIM1 KO neurons, but GluA1 and GluA3 protein levels are not altered in KO mice, indicating a regulatory role of STIM1 in AMPAR-mediated Ca2+ signaling in dorsal horn neurons. Together, our findings demonstrate that STIM1 plays an important role in the development of neuropathic pain via, at least in part, the regulation of AMPAR.