Store-operated Ca2+ entry in sensory neurons: functional role and the effect of painful nerve injury.
Store-operated Ca2+ entry in sensory neurons: functional role and the effect of painful nerve injury.
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DOI：
10.1523/jneurosci.5053-10.2011
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发表时间：
2011-03-09
期刊：
影响因子：
--
通讯作者：
Hogan QH
中科院分区：
文献类型：
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作者：
Gemes G;Bangaru ML;Wu HE;Tang Q;Weihrauch D;Koopmeiners AS;Cruikshank JM;Kwok WM;Hogan QH
疼痛性神经损伤破坏感觉神经元中细胞质和储存的Ca 2+水平。由于钙离子内流可能发生通过存储操作的钙离子进入（SOCE）以及电压和配体激活的途径，我们寻求确认SOCE在成年大鼠的感觉神经元，并检查是否SOCE功能障碍是一个可能的致病机制。背根神经节细胞内静息态Ca ~（2+）浓度下降，而重新引入Ca ~（2+）后，胞浆Ca ~（2+）浓度升高（40± 5 nM），这一变化可被毒胡萝卜素（1μM）消耗钙池放大，并可被SOCE阻断剂显著降低，但不受电压门控性膜Ca ~（2+）通道拮抗剂的影响。我们确定了潜在的内向整流Ca 2+依赖的ICRAC（Ca 2+释放激活电流），以及一个大的thapsiglene敏感的内向电流激活浴二价阳离子的撤回，代表SOCE。SOCE的分子组分，特别是STIM 1和Orai 1，在感觉神经元中在转录和蛋白质水平上都得到了证实。脊神经结扎（SNL）引起的轴索损伤增加了SOCE和ICRAC。然而，SOCE在受损和对照神经元中是相当的，当商店被毒胡萝卜素最大限度地耗尽时，STIM 1和Orai 1水平没有被SNL改变，这表明SNL后SOCE的上调是由商店耗尽驱动的。阻断SOCE增加了神经元的兴奋性，在控制和受伤的神经元，而受伤的神经元表现出特别的依赖SOCE维持细胞质和存储的Ca 2+的水平，这表明SOCE损伤后的补偿作用。
Painful nerve injury disrupts levels of cytoplasmic and stored Ca2+ in sensory neurons. Since influx of Ca2+ may occur through store-operated Ca2+ entry (SOCE) as well as voltage- and ligand-activated pathways, we sought confirmation of SOCE in sensory neurons from adult rats, and examined whether dysfunction of SOCE is a possible pathogenic mechanism. Dorsal root ganglion neurons displayed a fall in resting cytoplasmic Ca2+ concentration when bath Ca2+ was withdrawn, and a subsequent elevation of cytoplasmic Ca2+ concentration (40±5nM) when Ca2+ was reintroduced, which was amplified by store depletion with thapsigargin (1μM), and was significantly reduced by blockers of SOCE, but was unaffected by antagonists of voltage-gated membrane Ca2+ channels. We identified the underlying inwardly rectifying Ca2+-dependent ICRAC (Ca2+ release activated current), as well as a large thapsigargin-sensitive inward current activated by withdrawal of bath divalent cations, representing SOCE. Molecular components of SOCE, specifically STIM1 and Orai1, were confirmed in sensory neurons at both the transcript and protein levels. Axonal injury by spinal nerve ligation (SNL) elevated SOCE and ICRAC. However, SOCE was comparable in injured and control neurons when stores were maximally depleted by thapsigargin, and STIM1 and Orai1 levels were not altered by SNL, showing that upregulation of SOCE after SNL is driven by store depletion. Blockade of SOCE increased neuronal excitability in control and injured neurons, while injured neurons showed particular dependence on SOCE for maintaining levels of cytoplasmic and stored Ca2+, which indicates a compensatory role for SOCE following injury.