Journal
ACS CHEMICAL BIOLOGY
Volume 9, Issue 11, Pages 2496-2501Publisher
AMER CHEMICAL SOC
DOI: 10.1021/cb5005383
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Funding
- Ministerio de Economia y Competitividad [SAF2011-24779, CSD2008-00005, PCIN-2013-019-C03-03]
- ICREA Academia, Catalan Institution for Research and Advanced Studies
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) [R01 DK087688]
- NIDDK Intramural Research Program
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [ZIADK031117, R01DK087688] Funding Source: NIH RePORTER
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Caffeine, the most consumed psychoactive substance worldwide, may have beneficial effects on Parkinsons disease (PD) therapy. The mechanism by which caffeine contributes to its antiparkinsonian effects by acting as either an adenosine A(2A) receptor (A(2A)R) 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 A(2A)R agonist, of the receptors 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 A(2A)R 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
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