4.1 Article

Discovery of a macromolecular complex mediating the hunger suppressive actions of cocaine: Structural and functional properties

期刊

ADDICTION BIOLOGY
卷 26, 期 5, 页码 -

出版社

WILEY
DOI: 10.1111/adb.13017

关键词

anorexia; cocaine addiction; dopamine D-1 receptors; in silico modeling; sigma(1) receptors

资金

  1. Regional Catalonian Government [2017 SGR 1497]
  2. Spanish Ministry of Science and Innovation [SAF2015-74627-JIN, SAF2016-77830-R, BFU2015-64405-R]

向作者/读者索取更多资源

Cocaine affects dopamine levels in the brain and activates the sigma R-1 receptor, which regulates orexigenic receptor function. The macromolecular complex formed by sigma R-1, D1R, and GHS-R-1a is proposed to be altered by cocaine binding to the sigma R-1, affecting its functionality in coupling to Gs and Gq proteins. The expression of this complex is differentially affected by acute and chronic cocaine administration, potentially allowing dopamine to signal via Ca2+ and ghrelin via cAMP.
Cocaine not only increases brain dopamine levels but also activates the sigma(1) receptor (sigma R-1) that in turn regulates orexigenic receptor function. Identification of interactions involving dopamine D-1 (D1R), ghrelin (GHS-R-1a), and sigma(1) receptors have been addressed by biophysical techniques and a complementation approach using interfering peptides. The effect of cocaine on receptor functionality was assayed by measuring second messenger, cAMP and Ca2+, levels. The effect of acute or chronic cocaine administration on receptor complex expression was assayed by in situ proximity ligation assay. In silico procedures were used for molecular model building. sigma R-1 KO mice were used for confirming involvement of this receptor. Upon identification of protomer interaction and receptor functionality, a unique structural model for the macromolecular complex formed by sigma R-1, D1R, and GHS-R-1a is proposed. The functionality of the complex, able to couple to both Gs and Gq proteins, is affected by cocaine binding to the sigma R-1, as confirmed using samples from sigma R-1(-/-) mice. The expression of the macromolecular complex was differentially affected upon acute and chronic cocaine administration to rats. The constructed 3D model is consistent with biochemical, biophysical, and available structural data. The sigma R-1, D1R, and GHS-R-1a complex constitutes a functional unit that is altered upon cocaine binding to the sigma R-1. Remarkably, the heteromer can simultaneously couple to two G proteins, thus allowing dopamine to signal via Ca2+ and ghrelin via cAMP. The anorexic action of cocaine is mediated by such complex whose expression is higher after acute than after chronic administration regimens.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.1
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据