P2Y1 Receptor as a Catalyst of Brain Neurodegeneration

Different brain disorders display distinctive etiologies and pathogenic mechanisms. However, they also share pathogenic events. One event systematically occurring in different brain disorders, both acute and chronic, is the increase of the extracellular ATP levels. Accordingly, several P2 (ATP/ADP) and P1 (adenosine) receptors, as well as the ectoenzymes involved in the extracellular catabolism of ATP, have been associated to different brain pathologies, either with a neuroprotective or neurodegenerative action. The P2Y1 receptor (P2Y1R) is one of the purinergic receptors associated to different brain diseases. It has a widespread regional, cellular, and subcellular distribution in the brain, it is capable of modulating synaptic function and neuronal activity, and it is particularly important in the control of astrocytic activity and in astrocyte-neuron communication. In diverse brain pathologies, there is growing evidence of a noxious gain-of-function of P2Y1R favoring neurodegeneration by promoting astrocyte hyperactivity, entraining Ca²⁺-waves, and inducing the release of glutamate by directly or indirectly recruiting microglia and/or by increasing the susceptibility of neurons to damage. Here, we review the current evidence on the involvement of P2Y1R in different acute and chronic neurodegenerative brain disorders and the underlying mechanisms.