The sigma1 receptor interacts with N-alkyl amines and endogenous sphingolipids.
The sigma1 receptor interacts with N-alkyl amines and endogenous sphingolipids.
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DOI：
10.1016/j.ejphar.2009.03.003
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发表时间：
2009-05-01
影响因子：
5
通讯作者：
Ruoho AE
中科院分区：
文献类型：
--
作者：
Ramachandran S;Chu UB;Mavlyutov TA;Pal A;Pyne S;Ruoho AE
sigma1受体因其结合各种药物的能力而闻名，包括可卡因和甲基苯丙胺等滥用药物。一些内源性配体被认为是sigma1受体的调节剂。sigma1受体的高亲和力配体包含一个连接长烷基链的氮原子。我们发现，长烷基链伯胺，包括鞘脂家族的内源性胺，如d -红鞘氨酸和鞘氨酸，与sigma1受体结合具有相当大的亲和力，而与sigma2受体结合则没有亲和力。与放射性配体[3H]-(+)-戊唑嗪相比，d -红鞘氨醇与sigma1受体的结合在本质上似乎是竞争性的。有趣的是，研究充分的鞘脂介质鞘鞘醇-1磷酸不与sigma1或sigma2受体结合。鞘氨醇通过调节细胞中这两种生物活性脂质的相对水平的鞘氨醇激酶家族转化为鞘氨醇-1磷酸。鞘氨醇选择性结合而不是鞘氨醇-1磷酸与sigma1受体结合，提示鞘氨醇激酶调控sigma1受体活性的机制。我们成功地在过表达sigma1受体和鞘氨醇激酶-1的HEK-293细胞中重建了这个假设模型。本文提供的数据有力地支持鞘氨醇作为sigma1受体的内源性调节剂。
The sigma1 receptor is distinguished for its ability to bind various pharmacological agents including drugs of abuse such as cocaine and methamphetamine. Some endogenous ligands have been identified as putative sigma1 receptor regulators. High affinity ligands for the sigma1 receptor contain a nitrogen atom connected to long alkyl chains. We found that long alkyl chain primary amines including endogenous amines belonging to the sphingolipid family such as D-erythro-sphingosine and sphinganine bind with considerable affinity to the sigma1 receptor but not to the sigma2 receptor. The binding of D-erythro-sphingosine to the sigma1 receptor appears to be competitive in nature as assessed against the radioligand [3H]-(+)-pentazocine. Interestingly, the well studied sphingolipid mediator sphingosine-1 phosphate did not bind to the sigma1 or the sigma2 receptor. Sphingosine is converted to sphingosine-1 phosphate by a family of sphingosine kinases that regulate the relative levels of these two bioactive lipids in the cell. The selective binding of sphingosine but not sphingosine-1 phosphate to the sigma1 receptor suggests a mechanism for regulation of sigma1 receptor activity by the sphingosine kinase. We have successfully reconstituted this hypothetical model in HEK-293 cells overexpressing both the sigma1 receptor and sphingosine kinase-1. The data presented here strongly supports sphingosine as an endogenous modulator of the sigma1 receptor.
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DOI：
10.1126/science.1166127
发表时间：
2009-02-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fontanilla D;Johannessen M;Hajipour AR;Cozzi NV;Jackson MB;Ruoho AE
通讯作者：
Ruoho AE
DOI：
10.1073/pnas.0402890101
发表时间：
2004-10-12
影响因子：
11.1
作者：
Hayashi, T;Su, TP
通讯作者：
Su, TP
DOI：
10.1073/pnas.93.15.8072
发表时间：
1996-07-23
影响因子：
11.1
作者：
Hanner, M;Moebius, FF;Glossmann, H
通讯作者：
Glossmann, H
影响因子：
1.6
作者：
Ramachandran, Subramaniam;Lu, Hongliang;Ruoho, Arnold E.
通讯作者：
Ruoho, Arnold E.
影响因子：
4.8
作者：
Kohama, T;Olivera, A;Spiegel, S
通讯作者：
Spiegel, S