Modified 5-HT3A receptor function by co-expression of alternatively spliced human 5-HT3A receptor isoforms
Modified 5-HT3A receptor function by co-expression of alternatively spliced human 5-HT3A receptor isoforms
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DOI：
10.1007/s002100000342
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发表时间：
2000-11-01
影响因子：
3.6
通讯作者：
Bönisch, H
中科院分区：
文献类型：
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作者：
Brüss, M;Barann, M;Bönisch, H
5-羟色胺（5-HT）通过激活5-HT3受体而产生快速兴奋反应，无论它们是由5-HT3A亚基同质组成还是由5-HT3A和5-HT3B亚基异质组装。在这里，我们描述了人类5-HT3A （h5-HT3A）受体亚基的短，截断（h5-HT3AT）和长（h5-HT3AL）剪接变体。该短异构体由238个氨基酸（aa）和一个跨膜结构域（M1）组成。与已知的5-HT3A受体相比，长异构体在M2和M3之间的细胞外环中含有32个额外的aa。在杏仁核和海马中，这两种剪接变体都与5-HT3A亚基共表达，而在胎盘中，只有短变体共表达。当这两种剪接变体在转染的人胚胎肾（HEK） 293细胞中表达时，都不能形成功能性的同质受体，但可以改变异质h5-HT3A受体对5-HT的反应。短变异体的共表达显著减缓了5-HT3受体的脱敏；因此，h5-HT3A和h5-HT3AT亚基的异质组合表现出5- ht诱导的阳离子通量，远远大于同质h5-HT3A受体。相反，含有h5-HT3AL亚基的异相配合物显示出降低的阳离子通量。总之，剪接变异体增加了5-HT3受体的功能多样性。
Serotonin (5-HT) exerts fast excitatory responses by activation of 5-HT3 receptors, irrespective of whether they are homomerically composed of 5-HT3A subunits or heteromerically assembled of 5-HT3A and 5-HT3B subunits. Here we describe a short, truncated (h5-HT3AT) and a long (h5-HT3AL) splice variant of the human 5-HT3A (h5-HT3A) receptor subunit. The deduced protein of the short isoform consists of 238 amino acids (aa) with a single transmembrane domain (M1). Compared to the known 5-HT3A receptor, the long isoform contains 32 additional aa in the extracellular loop between M2 and M3. Both splice variants are co-expressed together with the 5-HT3A subunit in the amygdala and hippocampus, whereas in the placenta only the short variant is co-expressed. Both splice variants, when expressed in transfected human embryonic kidney (HEK) 293 cells, are not able to form functional homomeric receptors, but modify 5-HT response at heteromeric h5-HT3A receptors. Co-expression of the short variant considerably decelerates the desensitization of the 5-HT3 receptor; thus, heteromeric assemblies of h5-HT3A and the h5-HT3AT subunit exhibit 5-HT-induced cation fluxes which are much larger than those of homomeric h5-HT3A receptors. In contrast, heteromeric complexes containing the h5-HT3AL subunit display reduced cation fluxes. In conclusion, the splice variants increase the functional diversity of 5-HT3 receptors.