Human and animal studies have converged to suggest that caffeine consumption prevents memory deficits in aging and Alzheimer's disease through the antagonism of adenosine A2A receptors (A2ARs). To ...test if A2AR activation in the hippocampus is actually sufficient to impair memory function and to begin elucidating the intracellular pathways operated by A2AR, we have developed a chimeric rhodopsin-A2AR protein (optoA2AR), which retains the extracellular and transmembrane domains of rhodopsin (conferring light responsiveness and eliminating adenosine-binding pockets) fused to the intracellular loop of A2AR to confer specific A2AR signaling. The specificity of the optoA2AR signaling was confirmed by light-induced selective enhancement of cAMP and phospho-mitogen-activated protein kinase (p-MAPK) (but not cGMP) levels in human embryonic kidney 293 (HEK293) cells, which was abolished by a point mutation at the C terminal of A2AR. Supporting its physiological relevance, optoA2AR activation and the A2AR agonist CGS21680 produced similar activation of cAMP and p-MAPK signaling in HEK293 cells, of p-MAPK in the nucleus accumbens and of c-Fos/phosphorylated-CREB (p-CREB) in the hippocampus, and similarly enhanced long-term potentiation in the hippocampus. Remarkably, optoA2AR activation triggered a preferential p-CREB signaling in the hippocampus and impaired spatial memory performance, while optoA2AR activation in the nucleus accumbens triggered MAPK signaling and modulated locomotor activity. This shows that the recruitment of intracellular A2AR signaling in the hippocampus is sufficient to trigger memory dysfunction. Furthermore, the demonstration that the biased A2AR signaling and functions depend on intracellular A2AR loops prompts the possibility of targeting the intracellular A2AR-interacting partners to selectively control different neuropsychiatric behaviors.
Correction to: Molecular Psychiatry advance online publication, 17 February 2015; doi:10.1038/mp.2014.182 Following publication of the above article, the authors noticed that the seventeenth author’s ...name was listed incorrectly. The author’s name should have been listed as AP IJzerman. The publisherregrets the error.
Human and animal studies have converged to suggest that caffeine consumption prevents memory deficits in aging and Alzheimer's disease through the antagonism of adenosine A.sub.2A receptors ...(A.sub.2ARs). To test if A.sub.2AR activation in the hippocampus is actually sufficient to impair memory function and to begin elucidating the intracellular pathways operated by A.sub.2AR, we have developed a chimeric rhodopsin-A.sub.2AR protein (optoA.sub.2AR), which retains the extracellular and transmembrane domains of rhodopsin (conferring light responsiveness and eliminating adenosine-binding pockets) fused to the intracellular loop of A.sub.2AR to confer specific A.sub.2AR signaling. The specificity of the optoA.sub.2AR signaling was confirmed by light-induced selective enhancement of cAMP and phospho-mitogen-activated protein kinase (p-MAPK) (but not cGMP) levels in human embryonic kidney 293 (HEK293) cells, which was abolished by a point mutation at the C terminal of A.sub.2AR. Supporting its physiological relevance, optoA.sub.2AR activation and the A.sub.2AR agonist CGS21680 produced similar activation of cAMP and p-MAPK signaling in HEK293 cells, of p-MAPK in the nucleus accumbens and of c-Fos/phosphorylated-CREB (p-CREB) in the hippocampus, and similarly enhanced long-term potentiation in the hippocampus. Remarkably, optoA.sub.2AR activation triggered a preferential p-CREB signaling in the hippocampus and impaired spatial memory performance, while optoA.sub.2AR activation in the nucleus accumbens triggered MAPK signaling and modulated locomotor activity. This shows that the recruitment of intracellular A.sub.2AR signaling in the hippocampus is sufficient to trigger memory dysfunction. Furthermore, the demonstration that the biased A.sub.2AR signaling and functions depend on intracellular A.sub.2AR loops prompts the possibility of targeting the intracellular A.sub.2AR-interacting partners to selectively control different neuropsychiatric behaviors. Molecular Psychiatry (2015) 20, 1339-1349; doi: 10.1038/mp.2014.182; published online 17 February 2015
Human and animal studies have converged to suggest that caffeine consumption prevents memory deficits in aging and Alzheimer's disease through the antagonism of adenosine A sub(2A) receptors (A ...sub(2A)Rs). To test if A sub(2A)R activation in the hippocampus is actually sufficient to impair memory function and to begin elucidating the intracellular pathways operated by A sub(2A)R, we have developed a chimeric rhodopsin-A sub(2A)R protein (optoA sub(2A)R), which retains the extracellular and transmembrane domains of rhodopsin (conferring light responsiveness and eliminating adenosine-binding pockets) fused to the intracellular loop of A sub(2A)R to confer specific A sub(2A)R signaling. The specificity of the optoA sub(2A)R signaling was confirmed by light-induced selective enhancement of cAMP and phospho-mitogen-activated protein kinase (p-MAPK) (but not cGMP) levels in human embryonic kidney 293 (HEK293) cells, which was abolished by a point mutation at the C terminal of A sub(2A)R. Supporting its physiological relevance, optoA sub(2A)R activation and the A sub(2A)R agonist CGS21680 produced similar activation of cAMP and p-MAPK signaling in HEK293 cells, of p-MAPK in the nucleus accumbens and of c-Fos/phosphorylated-CREB (p-CREB) in the hippocampus, and similarly enhanced long-term potentiation in the hippocampus. Remarkably, optoA sub(2A)R activation triggered a preferential p-CREB signaling in the hippocampus and impaired spatial memory performance, while optoA sub(2A)R activation in the nucleus accumbens triggered MAPK signaling and modulated locomotor activity. This shows that the recruitment of intracellular A sub(2A)R signaling in the hippocampus is sufficient to trigger memory dysfunction. Furthermore, the demonstration that the biased A sub(2A)R signaling and functions depend on intracellular A sub(2A)R loops prompts the possibility of targeting the intracellular A sub(2A)R-interacting partners to selectively control different neuropsychiatric behaviors.
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