Orai1 Plays a Crucial Role in Central Sensitization by Modulating Neuronal Excitability

Abstract

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. Orai1 is a key component of store-operated calcium channels (SOCs) in many cell types. It has been implicated in such pathological conditions as immunodeficiency, autoimmunity, and cancer. However, the role of Orai1 in CNS disorders remains poorly understood. The 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 protein kinase C-extracellular signal-regulated protein kinase (PKC-ERK) pathway. Genetic knock-out of Orai1 nearly eliminates the second phase of formalin-induced pain and markedly attenuates carrageenan-induced pain hypersensitivity and neuronal excitability. These findings reveal a novel link between Orai1 and neuronal excitability and advance our understanding of central sensitization.

Endoplasmic reticulum–mitochondria interplay in chronic pain: The calcium connection

“…In a series of experiments employing Orai1 knock-out animals, Dou et al. 121 showed that Orai1 contributed to neuronal hyperexcitability in the spinal cord and pain behaviors following formalin and carrageenan administration. In the periphery, knockdown of STIM1, STIM2, Orai1, and Orai3 were found to diminish SOCE in DRG neurons.…”

ORAI2 Down-Regulation Potentiates SOCE and Decreases Aβ42 Accumulation in Human Neuroglioma Cells

“…All three subunits are expressed both in neurons and glial cells [ 11 , 37 , 42 , 44 , 45 , 46 , 47 ]. In neurons, ORAI1 appears dispensable for SOCE [ 46 ], but it has been implicated in neuronal excitability [ 45 , 48 ], whereas ORAI2 seems to be part of a neuronal SOC (nSOC) based on TRPC6 and activated by STIM2, and its activity is impaired in mouse AD models [ 46 ]. In glial cells, SOCE plays a major role in the Ca 2+ -based excitability that characterizes these cells both in culture [ 14 , 42 , 47 , 49 ] and in situ [ 50 , 51 ] studies.…”

Calcium Deregulation and Mitochondrial Bioenergetics in GDAP1-Related CMT Disease

“…STIM1 and STIM2 are upregulated in the hippocampus of chronic epileptic mice and were found to be strongly expressed in hippocampal samples from a patient suffering from medial temporal lobe epilepsy [126]. This highlights a role for SOCE in somehow controlling neuronal network excitability, as proposed for dorsal horn neurons [127]. Expression of these two ER proteins was also found to be upregulated after induction of TBI in two different studies.…”