Neuronal P2X7 Receptors Revisited: Do They Really Exist?

Area of Science:

• Neuroscience
• Cell Biology
• Immunology

Background:

• P2X7 receptors (P2X7Rs) are ATP-sensitive ionotropic channels with a unique C terminus.
• Their role in neuroinflammation, stroke, epilepsy, pain, and neurodegeneration is debated.
• The existence of neuronal P2X7Rs is contested, with recent focus on glial P2X7Rs.

Purpose of the Study:

• To re-evaluate the evidence for neuronal P2X7R function.
• To propose an alternative explanation for previously observed neuronal effects.
• To highlight the role of glial P2X7Rs in pathological conditions.

Main Methods:

• Review and critical analysis of existing literature on P2X7R localization and function.
• Consideration of recent findings on astrocyte-neuron and microglia-neuron communication.
• Evaluation of limitations in current research tools, including P2X7R agonists and antibodies.
• Assessment of P2RX7 knockout mouse models and their limitations.

Main Results:

• Existing tools lack selectivity, hindering definitive conclusions about P2X7R localization.
• Glial P2X7Rs (astrocytic and microglial) are increasingly implicated in neuronal effects.
• A bidirectional dialogue exists between glial cells and neurons.
• Neuronal P2X7R function cannot be entirely excluded but glial P2X7Rs offer a compelling alternative explanation.

Conclusions:

• Astrocytic and microglial P2X7Rs are likely primary targets of high extracellular ATP.
• These glial P2X7Rs may indirectly mediate neuronal effects previously attributed to neuronal P2X7Rs.
• Further research with improved tools is needed to definitively resolve the neuronal P2X7R debate.