title: ATP as a multi-target danger signal in the brain.
abstract: ATP is released in an activity-dependent manner from different cell types in the brain, fulfilling different roles as a neurotransmitter, neuromodulator, in astrocyte-to-neuron communication, propagating astrocytic responses and formatting microglia responses. This involves the activation of different ATP P2 receptors (P2R) as well as adenosine receptors upon extracellular ATP catabolism by ecto-nucleotidases. Notably, brain noxious stimuli trigger a sustained increase of extracellular ATP, which plays a key role as danger signal in the brain. This involves a combined action of extracellular ATP in different cell types, namely increasing the susceptibility of neurons to damage, promoting astrogliosis and recruiting and formatting microglia to mount neuroinflammatory responses. Such actions involve the activation of different receptors, as heralded by neuroprotective effects resulting from blockade mainly of P2X7R, P2Y1R and adenosine A2A receptors (A2AR), which hierarchy, cooperation and/or redundancy is still not resolved. These pleiotropic functions of ATP as a danger signal in brain damage prompt a therapeutic interest to multi-target different purinergic receptors to provide maximal opportunities for neuroprotection.
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra Coimbra, Portugal ; Institute for Interdisciplinary Research, University of Coimbra Coimbra, Portugal.
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Rodrigues
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra Coimbra, Portugal ; Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra Coimbra, Portugal.
authors.forename: Angelo R
authors.initials: AR
authors.lastname: Tomé
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra Coimbra, Portugal ; Faculty of Medicine, University of Coimbra Coimbra, Portugal.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Cunha
keywords: A2A receptor; ATP; P1 receptors; P2 receptors; P2X7 receptor; P2Y1 receptor; adenosine; ecto-nucleotidases