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Published on: November 15, 2024
Ethanol differentially modulates P2X4 and P2X7 receptor activity and function in BV2 microglial cells
Liana Asatryan1, Olga Ostrovskaya2, Dustin Lieu1
1Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA 90033, United States.
Abstract:
Neuroinflammation is one of the mechanisms leading to neurodegenerative brain damage induced by chronic alcohol (ethanol) exposure. Microglia play a major role in the development of innate immune responses to environmental injuries including ethanol. Adenosine 5″-triphosphate (ATP)-activated purinergic P2X receptor (P2XR) subtypes, P2X4Rs and P2X7Rs, are endogenously expressed in microglia and can modulate their activity. These 2 P2XR subtypes differ pharmacologically and functionally: 1) P2X4Rs are activated at lower (≤0.1 mM) whereas P2X7Rs - at higher (≥1.0 mM) ATP concentrations; 2) P2X4R activation contributes to the release of brain derived neurotrophic factor and its role in tactile allodynia and neuropathic pain is demonstrated; 3) Due to its role in the secretion of pro-inflammatory IL-1β, P2X7Rs have been implicated in the development of neurodegenerative pathologies, pain and morphine tolerance. To date, the roles of individual P2XR subtypes in ethanol effects on microglia and the functional consequences are not completely understood. Based on the existing knowledge on the pharmacological and functional differences between P2X4Rs and P2X7Rs, the present work tested the hypothesis that P2X4Rs and P2X7Rs play differential roles in ethanol action in microglia. Effects of ethanol on P2X4R and P2X7R activity, expression and functional consequences were determined using murine BV2 microglial cells. Ethanol (≥100 mM) inhibited P2X4Rs but was inactive on P2X7 channel activity. Ethanol (25, 100 mM) inhibited P2X4R-mediated microglia migration whereas it potentiated pore formation in P2X7Rs. Furthermore, ethanol (25, 100 mM) potentiated P2X7R-mediated IL-1β secretion from BV2 microglia. Ethanol also induced protein expression for both P2XR subtypes. Overall, the findings identify differential roles for P2X4Rs and P2X7Rs in regards to ethanol effects on microglia which may be linked to different stages of ethanol exposure.
Insights
Chronic alcohol exposure triggers neuroinflammation via microglia. This study reveals that ethanol differentially affects purinergic P2X4 receptors and P2X7 receptors in microglia, impacting neurodegenerative processes.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Neuroinflammation is a key mechanism in alcohol-induced neurodegeneration.
- Microglia are central to innate immune responses in the brain.
- Purinergic P2X receptors (P2X4Rs and P2X7Rs) on microglia modulate immune responses.
Purpose of the Study:
- To investigate the differential roles of P2X4Rs and P2X7Rs in ethanol's effects on microglia.
- To understand the functional consequences of ethanol's interaction with these receptors.
Main Methods:
- Utilized murine BV2 microglial cells to study ethanol's effects.
- Assessed P2X4R and P2X7R activity, expression, and functional outcomes.
- Measured microglia migration, pore formation, and IL-1β secretion.
Main Results:
- Ethanol (≥100 mM) inhibited P2X4R activity but not P2X7R channel activity.
- Ethanol inhibited P2X4R-mediated microglia migration but potentiated P2X7R pore formation.
- Ethanol enhanced P2X7R-mediated IL-1β secretion and increased expression of both P2XR subtypes.
Conclusions:
- P2X4Rs and P2X7Rs exhibit distinct responses to ethanol in microglia.
- These differential roles may be associated with various stages of alcohol exposure and neuroinflammation.
