Isolation and characterization of new exon 11-associated N-terminal splice variants of the human mu opioid receptor gene.
Isolation and characterization of new exon 11-associated N-terminal splice variants of the human mu opioid receptor gene.
复制标题
DOI：
10.1111/j.1471-4159.2008.05833.x
复制
发表时间：
2009-02
影响因子：
4.7
通讯作者：
Pan YX
中科院分区：
文献类型：
--
作者：
Xu J;Xu M;Hurd YL;Pasternak GW;Pan YX
在动物和人类中，已经证明了通过选择性剪接Mu阿片受体基因来创建多种Mu受体亚型。此前，我们在小鼠、大鼠和人类中发现了一些C末端变体，随后在小鼠中发现了几个与新的上游外显子(外显子11)相关的N末端变体。外显子11基因敲除小鼠的行为学研究表明，外显子11变异在海洛因和吗啡-6β-葡萄糖醛酸苷的止痛作用中起着重要作用，但不包括吗啡或美沙酮。我们现在已经确定了一个同源的人类外显子11和三个类似的人类外显子11相关变体，这表明外显子11及其相关变体在物种中是保守的。HMOR-1I在N-末端另外有93个氨基酸，但在其他方面与hMOR-1相同。当在中国仓鼠卵巢细胞中表达时，hMOR-1I中的93个氨基酸对阿片结合几乎没有影响，但显著改变了激动剂诱导的G蛋白激活。HMOR-1G1和hMOR-1G2预测了6个跨膜结构域变体，与在小鼠中看到的类似。通过RT-PCR检测，这些外显子11相关变异体的区域表达明显不同，这意味着区域特异性选择性剪接。人类外显子11相关变异的存在引发了人们对它们在海洛因和吗啡-6β-葡萄糖醛酸苷作用中的潜在作用的疑问，就像它们在老鼠身上所做的那样。
Alternative splicing of the mu opioid receptor genes to create multiple mu receptor subtypes has been demonstrated in animals and humans. Previously, we identified a number of C-terminal variants in mice, rats and human, followed by several N-terminal variants associated with a new upstream exon in mice (exon 11). Behavioral studies in exon 11 knockout mice suggest an important role for the exon 11 variants in the analgesic actions of heroin and morphine-6β-glucuronide, but not morphine or methadone. We now have identified a homologous human exon 11 and three similar human exon 11-associated variants, suggesting conservation of exon 11 and its associated variants across species. hMOR-1i has an additional 93 amino acids at the tip of the N-terminus but is otherwise identical to hMOR-1. When expressed in Chinese hamster ovary cells, the additional 93 amino acids in hMOR-1i had little effect on opioid binding, but significantly altered agonist-induced G-protein activation. hMOR-1G1 and hMOR-1G2 predicted six transmembrane domain variants, similar to those seen in mice. The regional expression of these exon 11-associated variants, as determined by RT-PCR, varied markedly, implying region-specific alternative splicing. The presence of exon 11-associated variants in humans raises questions regarding their potential role in heroin and morphine-6β-glucuronide actions in people as they do in mice.
登录
查看更多内容
影响因子：
3.5
作者：
Doyle, Glenn A.;Sheng, X. Rebecca;Berrettini, Wade H.
通讯作者：
Berrettini, Wade H.
影响因子：
64.8
作者：
LORD, JAH;WATERFIELD, AA;KOSTERLITZ, HW
通讯作者：
KOSTERLITZ, HW
影响因子：
3.3
作者：
Abbadie, C;Pasternak, GW;Aicher, SA
通讯作者：
Aicher, SA
影响因子：
2.3
作者：
Bolan, EA;Pan, YX;Pasternak, GW
通讯作者：
Pasternak, GW
影响因子：
4.4
作者：
Cadet, P;Mantione, KJ;Stefano, GB
通讯作者：
Stefano, GB