Gain and loss of function of P2X7 receptors: mechanisms, pharmacology and relevance to diabetic neuropathic pain.
Gain and loss of function of P2X7 receptors: mechanisms, pharmacology and relevance to diabetic neuropathic pain.
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DOI：
10.1186/1744-8069-10-37
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发表时间：
2014-06-16
期刊：
影响因子：
3.3
通讯作者：
Sher E
中科院分区：
文献类型：
--
作者：
Ursu D;Ebert P;Langron E;Ruble C;Munsie L;Zou W;Fijal B;Qian YW;McNearney TA;Mogg A;Grubisha O;Merchant K;Sher E
人类对疼痛的敏感性被夸大或降低的遗传原因是众所周知的。最近，编码ATP门控离子通道P2X7的基因P2RX7的单核苷酸多态性(SNPs)被描述为分别导致该通道的功能增益(GOF)和功能丧失(LOF)。重要的是，在患有乳腺癌术后疼痛和骨关节炎的患者中，P2RX7 SNPs与或多或少严重的疼痛评分有关。研究了一些P2RX7 SNP(rs208294(His155Tyr)、rs1718119(Ala348Thr)和rs3751143(Glu496Ala))在体外重组细胞中的功能后果。我们的发现表明，P2X7的GOF和LOF与实际的通道蛋白表达之间存在相关性。这些突变的P2X7受体的通道和孔功能都随着蛋白质水平的变化而变化。另一方面，突变受体对已知的P2X7激动剂和拮抗剂的敏感性没有差异。我们进一步证明，在糖尿病周围神经病理性疼痛(DPNP)患者中，GOF SNPs rs208294(His155Tyr)和rs1718119(Ala348Thr)的存在与女性患者的疼痛强度评分较高相关。我们目前的结果证实了P2RX7基因中一些SNP的生理学相关性，并表明这些遗传变异的存在与疼痛敏感性相关，在糖尿病神经病理性疼痛患者群体中也是如此。
Genetic causes of exaggerated or reduced pain sensitivity in humans are well known. Recently, single nucleotide polymorphisms (SNPs) in the gene P2RX7, coding for the ATP-gated ion channel P2X7, have been described that cause gain-of-function (GOF) and loss-of-function (LOF), respectively of this channel. Importantly, P2RX7 SNPs have been associated with more or less severe pain scores in patient suffering of post-mastectomy pain and osteoarthritis. The functional consequences of some P2RX7 SNPs (rs208294 (His155Tyr), rs1718119 (Ala348Thr) and rs3751143 (Glu496Ala)) were studied in recombinant cells in vitro. Our findings suggest a correlation between GOF and LOF of P2X7 and actual channel protein expression. Both channel and pore function for these mutant P2X7 receptors changed in parallel to protein levels. On the other hand, the mutant receptors did not differ in their sensitivity to known P2X7 agonists and antagonists. We further demonstrated that in patients with diabetic peripheral neuropathic pain (DPNP), the presence of the GOF SNPs rs208294 (His155Tyr) and rs1718119 (Ala348Thr) is associated, in females, with higher pain intensity scores. Our present results confirm the physiological relevance of some of the SNPs in the P2RX7 gene and show that the presence of these genetic variants correlates with pain sensitivity also in a diabetic neuropathic pain patient population.
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影响因子：
3.4
作者：
McHugh, Simon M.;Roman, Shilina;Bullmore, Edward T.
通讯作者：
Bullmore, Edward T.
影响因子：
6.4
作者：
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DOI：
10.1038/ejhg.2011.245
发表时间：
2012-05
期刊：
European journal of human genetics : EJHG
影响因子：
--
作者：
通讯作者：
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影响因子：
3.3
作者：
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通讯作者：
Schell, Kathleen
影响因子：
64.8
作者：
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通讯作者：
Gouaux, Eric