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 non-excitable 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 central nervous system (CNS) disorders has been relatively unexplored. Orai1 is a key component of SOCs and 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 that are involved in pain plasticity. Using both male and female Orai1 knockout mice, we found that activation of Orai1 increased neuronal excitability and reduced A-type potassium channels via the 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 sensory hypersensitivity and completely 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 pain process and central sensitization. Our study also reveals a novel link among Orai1, ERK, A-type potassium channels and neuronal excitability.Significance StatementOrai1 is a key component of store-operated calcium channels (SOCs) in many cell types. It has been implicated in pathological conditions including immunodeficiency, autoimmunity and cancer. However, the role of Orai1 in CNS disorders remains poorly understood. Functional significance of Orai1 in neurons is elusive. Here we demonstrate that activation of Orai1 modulates neuronal excitability and Kv4 containing A-type potassium channels via the PKC-ERK pathway. Genetic knockout of Orai1 nearly eliminates the second phase of formalin-induced pain and markedly attenuates carrageenan-induced sensory hypersensitivity and neuronal excitability. These findings reveal a novel link between Orai1 and neuronal excitability and advance our understanding of central sensitization.
Pharmacology, Toxicology and Pharmaceutical Science
3
9%
Medicine and Dentistry
3
9%
Other
4
12%
Unknown
5
15%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 02 August 2018.
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#22,340,091
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#17,097
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#295,097
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Outputs of similar age from Journal of Neuroscience
#169
of 242 outputs
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