TY - JOUR
T1 - Orai1 plays a crucial role in central sensitization by modulating neuronal excitability
AU - Dou, Yannong
AU - Ia, Jingsheng
AU - Gao, Ruby
AU - Gao, Inghua
AU - Munoz, Frances M.
AU - Wei, Dongyu
AU - Tian, Yuzhen
AU - Barrett, James E.
AU - Ajit, Seena
AU - Meucci, Olimpia
AU - Putney, James W.
AU - Dai, Yue
AU - Hu, Huijuan
N1 - Funding Information:
Received Oct. 18, 2017; revised Nov. 19, 2017; accepted Nov. 29, 2017. Author contributions: Y. Dou, S.A., Y. Dai, and H.H. designed research; Y. Dou, J.X., R.G., X.G., F.M.M., D.W., and Y.T.performedresearch;J.E.B.,O.M.,andJ.W.P.contributedunpublishedreagents/analytictools;Y.Dou,J.X.,R.G., X.G., F.M.M., and H.H. analyzed data; Y. Dou, J.E.B., Y. Dai, and H.H. wrote the paper. This work was supported by National Institutes of Health Grants R21NS077330 and R01NS087033 (to H.H.). We thank Dr. Donald Gill (Penn State College of Medicine) for providing Orai1-CFP. The authors declare no competing financial interests.
Publisher Copyright:
© 2018 the authors.
PY - 2018/1/24
Y1 - 2018/1/24
N2 - Pathological pain is a common and debilitating condition that is often poorly managed. Central sensitization is an important mechanism underlying pathological pain. However, candidate molecules involved in central sensitization remain unclear. Store-operated calcium channels (SOCs) mediate important calcium signals in nonexcitable and excitable cells. SOCs have been implicated in a wide variety of human pathophysiological conditions, including immunodeficiency, occlusive vascular diseases, and cancer. However, the role of SOCs in CNS disorders has been relatively unexplored. Orai1, a key component of SOCs, is expressed in the human and rodent spinal cord dorsal horn, but its functional significance in dorsal horn neurons is poorly understood. Here we sought to explore a potential role of Orai1 in the modulation of neuronal excitability and A-type potassium channels involved in pain plasticity. Using both male and female Orai1 knock-out mice, we found that activation of Orai1 increased neuronal excitability and reduced A-type potassium channels via the protein kinase C–extracellular signal-regulated protein kinase (PKC–ERK) pathway in dorsal horn neurons. Orai1 deficiency significantly decreased acute pain induced by noxious stimuli, nearly eliminated the second phase of formalin-induced nociceptive response, markedly attenuated carrageenan-induced ipsilateral pain hypersensitivity and abolished carrageenan-induced contralateral mechanical allodynia. Consistently, carrageenan-induced increase in neuronal excitability was abolished in the dorsal horn from Orai1 mutant mice. These findings uncover a novel signaling pathway involved in the pain process and central sensitization. Our study also reveals a novel link among Orai1, ERK, A-type potassium channels, and neuronal excitability.
AB - Pathological pain is a common and debilitating condition that is often poorly managed. Central sensitization is an important mechanism underlying pathological pain. However, candidate molecules involved in central sensitization remain unclear. Store-operated calcium channels (SOCs) mediate important calcium signals in nonexcitable and excitable cells. SOCs have been implicated in a wide variety of human pathophysiological conditions, including immunodeficiency, occlusive vascular diseases, and cancer. However, the role of SOCs in CNS disorders has been relatively unexplored. Orai1, a key component of SOCs, is expressed in the human and rodent spinal cord dorsal horn, but its functional significance in dorsal horn neurons is poorly understood. Here we sought to explore a potential role of Orai1 in the modulation of neuronal excitability and A-type potassium channels involved in pain plasticity. Using both male and female Orai1 knock-out mice, we found that activation of Orai1 increased neuronal excitability and reduced A-type potassium channels via the protein kinase C–extracellular signal-regulated protein kinase (PKC–ERK) pathway in dorsal horn neurons. Orai1 deficiency significantly decreased acute pain induced by noxious stimuli, nearly eliminated the second phase of formalin-induced nociceptive response, markedly attenuated carrageenan-induced ipsilateral pain hypersensitivity and abolished carrageenan-induced contralateral mechanical allodynia. Consistently, carrageenan-induced increase in neuronal excitability was abolished in the dorsal horn from Orai1 mutant mice. These findings uncover a novel signaling pathway involved in the pain process and central sensitization. Our study also reveals a novel link among Orai1, ERK, A-type potassium channels, and neuronal excitability.
KW - A-type potassium channels
KW - ERK
KW - Orai1
KW - Pain
KW - Spinal cord dorsal horn
KW - Store-operated calcium channels
UR - http://www.scopus.com/inward/record.url?scp=85041008882&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041008882&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.3007-17.2017
DO - 10.1523/JNEUROSCI.3007-17.2017
M3 - Article
C2 - 29229703
AN - SCOPUS:85041008882
VL - 38
SP - 887
EP - 900
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 4
ER -