The P2Y12 receptor regulates microglial activation by extracellular nucleotides
Abstract
Microglia are primary immune sentinels of the CNS. Following injury, these cells migrate or extend processes toward sites of tissue damage. CNS injury is accompanied by release of nucleotides, serving as signals for microglial activation or chemotaxis. Microglia express several purinoceptors, including a G(i)-coupled subtype that has been implicated in ATP- and ADP-mediated migration in vitro. Here we show that microglia from mice lacking G(i)-coupled P2Y(12) receptors exhibit normal baseline motility but are unable to polarize, migrate or extend processes toward nucleotides in vitro or in vivo. Microglia in P2ry(12)(-/-) mice show significantly diminished directional branch extension toward sites of cortical damage in the living mouse. Moreover, P2Y(12) expression is robust in the 'resting' state, but dramatically reduced after microglial activation. These results imply that P2Y(12) is a primary site at which nucleotides act to induce microglial chemotaxis at early stages of the response to local CNS injury.
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P2RY12 expression is lost upon microglia activation and culture.
“P2RY12 expression is lost upon microglia activation74, culture34”
From Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies (2022) · cites this paper as [74]
Microglial identity eventually decays in cultured brain slices.
“Thus, preservation of the CNS environment can delay loss of microglial signature gene expression ex vivo although microglial identity does eventually decay in cultured brain slices (Haynes et al., 2006).”
From Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures (2017) · cites this paper as Haynes et al., 2006
P2RY12 expression is decreased and lost in macrophages that exhibit an inflammatory phenotype.
“Moreover, P2RY12 expression is decreased and lost in macrophages that exhibit an inflammatory phenotype [19, 31].”
From Loss of homeostatic microglial phenotype in CSF1R-related Leukoencephalopathy (2020) · cites this paper as [19]
Microglia express a broad spectrum of neurotransmitter receptors and ion channels that critically regulate microglial functions such as surveillance, cytokine release, chemotaxis, and phagocytosis.
“Microglia express a broad spectrum of neurotransmitter receptors and ion channels that critically regulate microglial functions such as surveillance (Madry et al., 2018), cytokine release (Nguyen et al., 2017), chemotaxis, and phagocytosis (Haynes et al., 2006; Koizumi et al., 2007; Ohsawa et al., 2007).”
From Overexpressing low‐density lipoprotein receptor reduces tau‐associated neurodegeneration in relation to apoE‐linked mechanisms (2021) · cites this paper as Haynes et al., 2006
Microglia use nearly 100 genes, their sensome, to detect microenvironment changes; this includes P2yr12, AXL, and MER.
“They use the products of nearly 100 genes to sense changes in their microenvironment (their sensome) including P2yr12, AXL, and MER4,7,19”
From Microglia in neurodegeneration (2018) · cites this paper as [4]
Mature pMGLs stained positive for markers of murine and human microglia, with TMEM119 and P2RY12 displaying broad membrane and punctate vesicular expression.
“Mature pMGLs stained positive for markers of murine and human microglia 10,11,29,30, with both TMEM119 and P2RY12 displaying a broad membrane and punctate vesicular expression pattern”
From Efficient derivation of microglia-like cells from human pluripotent stem cells (2016) · cites this paper as [30]
P2Y12 is selectively expressed in non-activated microglia.
“we focused on the P2Y12 purinergic receptor, which is selectively expressed in non-activated microglia and mediates process motility during early injury responses.”
From Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex (2016) · cites this paper as [21]
P2Y12 mediates process motility during early injury responses.
“we focused on the P2Y12 purinergic receptor, which is selectively expressed in non-activated microglia and mediates process motility during early injury responses.”
From Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex (2016) · cites this paper as [21]
P2Y12 expression correlates strongly with ramified microglial morphology characteristic of healthy neurophysiology.
“In addition, its expression correlates strongly with a ramified microglial morphology characteristic of healthy neurophysiology, indicating that it primarily functions during rapid responses to perturbations of brain homeostasis2123.”
From Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex (2016) · cites this paper as [21]
P2Y12 elicits rapid and pronounced chemotactic responses of microglial processes.
“P2Y12 is highly sensitive to adenosine diphosphate, abundantly and selectively expressed in homeostatic microglia, rapidly downregulated following the initiation of inflammation and elicits rapid and pronounced chemotactic responses of microglial processes2122.”
From Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex (2016) · cites this paper as [21]
Activation of the Gi/o-coupled purinergic receptor P2Y12 powerfully alters microglial dynamics in vivo.
“The microglial expression of most of these receptors has been demonstrated in vitro, but activation of the Gi/o-coupled purinergic receptor, P2Y12, has been shown to powerfully alter microglial dynamics in vivo21.”
From Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex (2016) · cites this paper as [21]
P2Y12 is rapidly downregulated following initiation of inflammation.
“P2Y12 is highly sensitive to adenosine diphosphate, abundantly and selectively expressed in homeostatic microglia, rapidly downregulated following the initiation of inflammation and elicits rapid and pronounced chemotactic responses of microglial processes2122.”
From Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex (2016) · cites this paper as [21]
P2Y12 is highly sensitive to adenosine diphosphate.
“P2Y12 is highly sensitive to adenosine diphosphate, abundantly and selectively expressed in homeostatic microglia, rapidly downregulated following the initiation of inflammation and elicits rapid and pronounced chemotactic responses of microglial processes2122.”
From Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex (2016) · cites this paper as [21]
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- Authors
- Haynes, S. E., Hollopeter, G., Yang, G., Kurpius, D., Dailey, M. E., Gan, W.-B., & Julius, D.
- Affiliations
- University of California, San Francisco (US)
- New York University (US)
- University of Iowa (US)
- Corresponding author
- Julius, David
- Venue
- Nature Neuroscience
- Published
- 2006-11-19
- Volume
- 9
- Issue
- 12
- Pages
- 1512-1519
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W2131686384
- Cited by
- 1,542
- References
- 34
- Citations by year
- 2026: 91 · 2025: 80 · 2024: 126 · 2023: 94 · 2022: 122 · 2021: 138 · 2020: 104 · 2019: 93 · 2018: 80 · 2017: 71 · 2016: 63 · 2015: 68 · 2014: 64 · 2013: 67 · 2012: 69
- FWCI
- 19.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- University of California, San Francisco
- National Institute of Neurological Disorders and Stroke (R01NS043468, NS434468)
- National Center for Research Resources (S10RR017941)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- P2Y12 receptor, microglial activation, extracellular nucleotides, microglial chemotaxis, microglial polarization, microglial motility, purinergic signaling, G protein-coupled receptors, central nervous system injury, cortical injury
- MeSH terms
- Adenosine Diphosphate, Adenosine Triphosphate, Animals, Brain Injuries, Central Nervous System, Chemotaxis, Membrane Proteins, Microglia, Receptors, Purinergic P2, Mice, Knockout, Mice, Receptors, Purinergic P2Y12
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