Differential activation of mouse and human Panx1 channel variants.
Differential activation of mouse and human Panx1 channel variants.
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DOI：
10.1371/journal.pone.0295710
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发表时间：
2023
期刊：
影响因子：
3.7
通讯作者：
Scemes E
中科院分区：
文献类型：
--
作者：
Cibelli A;Dohare P;Spray DC;Scemes E
Pannexins在人和小鼠组织中普遍表达。PAnnexin 1(Panx1)是该家族中特征最全面的成员，形成可被相对较大的分子(如ATP)渗透的质膜通道。尽管人类和小鼠的Panx1氨基酸序列在目前已知的参与通道运输和调控的调控位点上是保守的，但据报道，该蛋白的N-末端和C-末端存在差异，不同刺激激活通道的机制仍然存在争议。在这里，我们使用神经母细胞瘤细胞系来研究内源性mPanx1和外源性表达hPanx1的激活特性。染料摄取和电生理记录显示，与小鼠Panx1不同，人类同源基因对高细胞外[K+]刺激不敏感，但对嘌呤能P2X7受体的激活反应相似。在人群中发现的两个最常见的Panx1多态，Q5H(Rs1138800)和E390D(Rs74549886)，在Panx1缺失的N2a细胞中外源表达，表明对于P2X7受体介导的Panx1激活，Q5H突变是功能获得，而E390D突变是功能缺失变体。总而言之，我们展示了人和小鼠Panx1同源基因在激活方面的差异，并建议这些差异可能对Panx1已被证明具有显著影响的研究具有翻译意义。
Pannexins are ubiquitously expressed in human and mouse tissues. Pannexin 1 (Panx1), the most thoroughly characterized member of this family, forms plasmalemmal membrane channels permeable to relatively large molecules, such as ATP. Although human and mouse Panx1 amino acid sequences are conserved in the presently known regulatory sites involved in trafficking and modulation of the channel, differences are reported in the N- and C-termini of the protein, and the mechanisms of channel activation by different stimuli remain controversial. Here we used a neuroblastoma cell line to study the activation properties of endogenous mPanx1 and exogenously expressed hPanx1. Dye uptake and electrophysiological recordings revealed that in contrast to mouse Panx1, the human ortholog is insensitive to stimulation with high extracellular [K+] but responds similarly to activation of the purinergic P2X7 receptor. The two most frequent Panx1 polymorphisms found in the human population, Q5H (rs1138800) and E390D (rs74549886), exogenously expressed in Panx1-null N2a cells revealed that regarding P2X7 receptor mediated Panx1 activation, the Q5H mutant is a gain of function whereas the E390D mutant is a loss of function variant. Collectively, we demonstrate differences in the activation between human and mouse Panx1 orthologs and suggest that these differences may have translational implications for studies where Panx1 has been shown to have significant impact.
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