Native store-operated calcium channels are functionally expressed in mouse spinal cord dorsal horn neurons and regulate resting calcium homeostasis

Jingsheng Xia, Rong Pan, Xinghua Gao, Olimpia Meucci, Huijuan Hu

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

A previous study indicates that store-operated calcium channels (SOCs) play a role in pain hypersensitivity. Here we report for the first time that SOCs are expressed and functional in spinal cord dorsal horn neurons. Using the small inhibitory RNA knockdown approach, we have demonstrated that Orai1 is necessary, and both STIM1 and STIM2 are important for SOC entry and SOC current in dorsal horn neurons. Our findings demonstrate that STIM1, STIM2 and Orai1 play an important role in resting Ca2+ homeostasis. Our results also indicate that SOCs are involved in the function of neurokinin 1 receptors and activation of SOCs produces an excitatory action in dorsal horn neurons. The present study reveals that a novel calcium signal mediated by SOCs is present in dorsal horn neurons and provides a potential mechanism for SOC inhibition-induced central analgesia. Store-operated calcium channels (SOCs) are calcium-selective cation channels that mediate calcium entry in many different cell types. Store-operated calcium entry (SOCE) is involved in various cellular functions. Increasing evidence suggests that impairment of SOCE is responsible for numerous disorders. A previous study demonstrated that YM-58483, a potent SOC inhibitor, strongly attenuates chronic pain by systemic or intrathecal injection and completely blocks the second phase of formalin-induced spontaneous nocifensive behaviour, suggesting a potential role of SOCs in central sensitization. However, the expression of SOCs, their molecular identity and function in spinal cord dorsal horn neurons remain elusive. Here, we demonstrate that SOCs are expressed in dorsal horn neurons. Depletion of calcium stores from the endoplasmic reticulum (ER) induced large sustained calcium entry, which was blocked by SOC inhibitors, but not by voltage-gated calcium channel blockers. Depletion of ER calcium stores activated inward calcium-selective currents, which was reduced by replacing Ca2+ with Ba2+ and reversed by SOC inhibitors. Using the small inhibitory RNA knockdown approach, we identified both STIM1 and STIM2 as important mediators of SOCE and SOC current, and Orai1 as a key component of the Ca2+ release-activated Ca2+ channels in dorsal horn neurons. Knockdown of STIM1, STIM2 or Orai1 decreased resting Ca2+ levels. We also found that activation of neurokinin 1 receptors led to SOCE and activation of SOCs produced an excitatory action in dorsal horn neurons. Our findings reveal that a novel SOC signal is present in dorsal horn neurons and may play an important role in pain transmission.

Original languageEnglish (US)
Pages (from-to)3443-3461
Number of pages19
JournalJournal of Physiology
Volume592
Issue number16
DOIs
StatePublished - Aug 15 2014

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Posterior Horn Cells
Calcium Channels
Homeostasis
Calcium
Spinal Cord Dorsal Horn
Neurokinin-1 Receptors
Endoplasmic Reticulum
RNA
Central Nervous System Sensitization
Pain
Spinal Injections

All Science Journal Classification (ASJC) codes

  • Physiology

Cite this

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title = "Native store-operated calcium channels are functionally expressed in mouse spinal cord dorsal horn neurons and regulate resting calcium homeostasis",
abstract = "A previous study indicates that store-operated calcium channels (SOCs) play a role in pain hypersensitivity. Here we report for the first time that SOCs are expressed and functional in spinal cord dorsal horn neurons. Using the small inhibitory RNA knockdown approach, we have demonstrated that Orai1 is necessary, and both STIM1 and STIM2 are important for SOC entry and SOC current in dorsal horn neurons. Our findings demonstrate that STIM1, STIM2 and Orai1 play an important role in resting Ca2+ homeostasis. Our results also indicate that SOCs are involved in the function of neurokinin 1 receptors and activation of SOCs produces an excitatory action in dorsal horn neurons. The present study reveals that a novel calcium signal mediated by SOCs is present in dorsal horn neurons and provides a potential mechanism for SOC inhibition-induced central analgesia. Store-operated calcium channels (SOCs) are calcium-selective cation channels that mediate calcium entry in many different cell types. Store-operated calcium entry (SOCE) is involved in various cellular functions. Increasing evidence suggests that impairment of SOCE is responsible for numerous disorders. A previous study demonstrated that YM-58483, a potent SOC inhibitor, strongly attenuates chronic pain by systemic or intrathecal injection and completely blocks the second phase of formalin-induced spontaneous nocifensive behaviour, suggesting a potential role of SOCs in central sensitization. However, the expression of SOCs, their molecular identity and function in spinal cord dorsal horn neurons remain elusive. Here, we demonstrate that SOCs are expressed in dorsal horn neurons. Depletion of calcium stores from the endoplasmic reticulum (ER) induced large sustained calcium entry, which was blocked by SOC inhibitors, but not by voltage-gated calcium channel blockers. Depletion of ER calcium stores activated inward calcium-selective currents, which was reduced by replacing Ca2+ with Ba2+ and reversed by SOC inhibitors. Using the small inhibitory RNA knockdown approach, we identified both STIM1 and STIM2 as important mediators of SOCE and SOC current, and Orai1 as a key component of the Ca2+ release-activated Ca2+ channels in dorsal horn neurons. Knockdown of STIM1, STIM2 or Orai1 decreased resting Ca2+ levels. We also found that activation of neurokinin 1 receptors led to SOCE and activation of SOCs produced an excitatory action in dorsal horn neurons. Our findings reveal that a novel SOC signal is present in dorsal horn neurons and may play an important role in pain transmission.",
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Native store-operated calcium channels are functionally expressed in mouse spinal cord dorsal horn neurons and regulate resting calcium homeostasis. / Xia, Jingsheng; Pan, Rong; Gao, Xinghua; Meucci, Olimpia; Hu, Huijuan.

In: Journal of Physiology, Vol. 592, No. 16, 15.08.2014, p. 3443-3461.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Native store-operated calcium channels are functionally expressed in mouse spinal cord dorsal horn neurons and regulate resting calcium homeostasis

AU - Xia, Jingsheng

AU - Pan, Rong

AU - Gao, Xinghua

AU - Meucci, Olimpia

AU - Hu, Huijuan

PY - 2014/8/15

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N2 - A previous study indicates that store-operated calcium channels (SOCs) play a role in pain hypersensitivity. Here we report for the first time that SOCs are expressed and functional in spinal cord dorsal horn neurons. Using the small inhibitory RNA knockdown approach, we have demonstrated that Orai1 is necessary, and both STIM1 and STIM2 are important for SOC entry and SOC current in dorsal horn neurons. Our findings demonstrate that STIM1, STIM2 and Orai1 play an important role in resting Ca2+ homeostasis. Our results also indicate that SOCs are involved in the function of neurokinin 1 receptors and activation of SOCs produces an excitatory action in dorsal horn neurons. The present study reveals that a novel calcium signal mediated by SOCs is present in dorsal horn neurons and provides a potential mechanism for SOC inhibition-induced central analgesia. Store-operated calcium channels (SOCs) are calcium-selective cation channels that mediate calcium entry in many different cell types. Store-operated calcium entry (SOCE) is involved in various cellular functions. Increasing evidence suggests that impairment of SOCE is responsible for numerous disorders. A previous study demonstrated that YM-58483, a potent SOC inhibitor, strongly attenuates chronic pain by systemic or intrathecal injection and completely blocks the second phase of formalin-induced spontaneous nocifensive behaviour, suggesting a potential role of SOCs in central sensitization. However, the expression of SOCs, their molecular identity and function in spinal cord dorsal horn neurons remain elusive. Here, we demonstrate that SOCs are expressed in dorsal horn neurons. Depletion of calcium stores from the endoplasmic reticulum (ER) induced large sustained calcium entry, which was blocked by SOC inhibitors, but not by voltage-gated calcium channel blockers. Depletion of ER calcium stores activated inward calcium-selective currents, which was reduced by replacing Ca2+ with Ba2+ and reversed by SOC inhibitors. Using the small inhibitory RNA knockdown approach, we identified both STIM1 and STIM2 as important mediators of SOCE and SOC current, and Orai1 as a key component of the Ca2+ release-activated Ca2+ channels in dorsal horn neurons. Knockdown of STIM1, STIM2 or Orai1 decreased resting Ca2+ levels. We also found that activation of neurokinin 1 receptors led to SOCE and activation of SOCs produced an excitatory action in dorsal horn neurons. Our findings reveal that a novel SOC signal is present in dorsal horn neurons and may play an important role in pain transmission.

AB - A previous study indicates that store-operated calcium channels (SOCs) play a role in pain hypersensitivity. Here we report for the first time that SOCs are expressed and functional in spinal cord dorsal horn neurons. Using the small inhibitory RNA knockdown approach, we have demonstrated that Orai1 is necessary, and both STIM1 and STIM2 are important for SOC entry and SOC current in dorsal horn neurons. Our findings demonstrate that STIM1, STIM2 and Orai1 play an important role in resting Ca2+ homeostasis. Our results also indicate that SOCs are involved in the function of neurokinin 1 receptors and activation of SOCs produces an excitatory action in dorsal horn neurons. The present study reveals that a novel calcium signal mediated by SOCs is present in dorsal horn neurons and provides a potential mechanism for SOC inhibition-induced central analgesia. Store-operated calcium channels (SOCs) are calcium-selective cation channels that mediate calcium entry in many different cell types. Store-operated calcium entry (SOCE) is involved in various cellular functions. Increasing evidence suggests that impairment of SOCE is responsible for numerous disorders. A previous study demonstrated that YM-58483, a potent SOC inhibitor, strongly attenuates chronic pain by systemic or intrathecal injection and completely blocks the second phase of formalin-induced spontaneous nocifensive behaviour, suggesting a potential role of SOCs in central sensitization. However, the expression of SOCs, their molecular identity and function in spinal cord dorsal horn neurons remain elusive. Here, we demonstrate that SOCs are expressed in dorsal horn neurons. Depletion of calcium stores from the endoplasmic reticulum (ER) induced large sustained calcium entry, which was blocked by SOC inhibitors, but not by voltage-gated calcium channel blockers. Depletion of ER calcium stores activated inward calcium-selective currents, which was reduced by replacing Ca2+ with Ba2+ and reversed by SOC inhibitors. Using the small inhibitory RNA knockdown approach, we identified both STIM1 and STIM2 as important mediators of SOCE and SOC current, and Orai1 as a key component of the Ca2+ release-activated Ca2+ channels in dorsal horn neurons. Knockdown of STIM1, STIM2 or Orai1 decreased resting Ca2+ levels. We also found that activation of neurokinin 1 receptors led to SOCE and activation of SOCs produced an excitatory action in dorsal horn neurons. Our findings reveal that a novel SOC signal is present in dorsal horn neurons and may play an important role in pain transmission.

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