From:  Mechanisms of astrocytic and microglial purinergic signaling in homeostatic regulation and implications for neurological disease

Mechanisms of purinergic signaling in neuron-astrocyte-microglia interactions

MechanismCell types involvedKey receptorsFunction/RoleReferences
Purinergic signaling in brain homeostasisAstrocytes, microglia, neuronsP2 receptors (P2Y1, P2Y12), A1Rs, A2ARsPurinergic signaling regulates synaptic pruning, neuroprotection, maintaining brain development, and homeostasis[75, 138, 139]
Neuron-astrocyte communication for homeostasisNeurons and astrocytesP2X, P2Y, A1Rs, A2ARsBidirectional communication: neurons release neurotransmitters causing Ca2+ changes in astrocytes, which release ATP to modulate synaptic activity and maintain brain homeostasis[44, 140, 141]
ATP in synaptic transmissionNeurons and astrocytesP2XRs, NMDA receptors, A1Rs, A2ARsATP mediates excitatory neurotransmission; P2XRs regulate synaptic plasticity, with roles in both LTP and synaptic depression[44, 142, 143]
Astrocytic ATP release and synaptic regulationAstrocytes and neuronsP2X, P2Y, A1Rs, A2ARsAstrocytes release ATP, influencing synaptic excitability, ion balance, and synaptic plasticity through interaction with adenosine receptors (A1Rs, A2ARs)[44, 144, 145]
Adenosine receptor interactionsAstrocytes and neuronsA1Rs, A2ARsA2ARs enhance NMDA receptor activity and glutamate release, while A1Rs inhibit synaptic transmission, offering neuroprotective effects[42, 146, 147]
ATP and calcium (Ca2+)-mediated communicationAstrocytesP2Y, P2XATP activates purinergic receptors (P2X, P2Y) to induce Ca2+ increases in astrocytes, propagating Ca2+ waves that influence synaptic modulation[148–150]
Neurovascular coupling and redox homeostasisAstrocytes and blood vesselsA1Rs, A2ARsAstrocytes regulate blood flow and redox balance in response to neuronal activity, utilizing ATP and adenosine signaling[151, 152]
Reactive astrocytes in injuryAstrocytesA1Rs, A2ARsDuring injury, ATP and adenosine modulate astrocytic responses: A1Rs suppress excessive excitation; A2ARs promote synaptic facilitation and inflammation[153, 154]
Microglial activation and neuroinflammatory responsesMicrogliaP2X4, P2Y12, A2ARATP activates microglia through P2X and P2Y receptors, initiating immune responses; P2X4Rs mediate pro-inflammatory responses, while P2Y12Rs guide microglial migration[155–157]
Adenosine modulation of microglial inflammationMicrogliaA2ARAdenosine via A2ARs counterbalances ATP-induced activation of microglia, reducing inflammation and promoting neuroprotection[157–160]
Astrocyte-microglia crosstalk during injuryAstrocytes and microgliaP2Y1, P2Y12ATP release from damaged cells activates purinergic receptors on both astrocytes and microglia, amplifying the inflammatory response and modulating synaptic activity[37, 75, 80]
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LTP: long-term potentiation