Uncovering Caffeine鈥檚 Adenosine A2A Receptor Inverse Agonism in Experimental Parkinsonism
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- 作者：V铆ctor Fern谩ndez-Due帽as ; Maricel G贸mez-Soler ; Marc L贸pez-Cano ; Jaume J. Taura ; Catherine Ledent ; Masahiko Watanabe ; Kenneth A. Jacobson ; Jean-Pierre Vilardaga ; Francisco Ciruela
- 刊名：ACS Chemical Biology
- 出版年：2014
- 出版时间：November 21, 2014
- 年：2014
- 卷：9
- 期：11
- 页码：2496-2501
- 全文大小：291K
- ISSN：1554-8937
文摘
Caffeine, the most consumed psychoactive substance worldwide, may have beneficial effects on Parkinson鈥檚 disease (PD) therapy. The mechanism by which caffeine contributes to its antiparkinsonian effects by acting as either an adenosine A2A receptor (A2AR) neutral antagonist or an inverse agonist is unresolved. Here we show that caffeine is an A2AR inverse agonist in cell-based functional studies and in experimental parkinsonism. Thus, we observed that caffeine triggers a distinct mode, opposite to A2AR agonist, of the receptor鈥檚 activation switch leading to suppression of its spontaneous activity. These inverse agonist-related effects were also determined in the striatum of a mouse model of PD, correlating well with increased caffeine-mediated motor effects. Overall, caffeine A2AR inverse agonism may be behind some of the well-known physiological effects of this substance both in health and disease. This information might have a critical mechanistic impact for PD pharmacotherapeutic design.