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Cited by 239Adenosine and Purinergic SignalingNeuroinflammation and Neurodegeneration MechanismsPain Mechanisms and Treatments

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Microglia and Neuroinflammation: What Place for P2RY12?

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Gómez Morillas, Albert, Besson, Valérie C., Lerouet, Dominique·2021·International Journal of Molecular Sciences
DOI 10.3390/ijms22041636PMC PMC7915979
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Abstract

Microglia are immune brain cells involved in neuroinflammation. They express a lot of proteins on their surface such as receptors that can be activated by mediators released in the microglial environment. Among these receptors, purinergic receptor expression could be modified depending on the activation status of microglia. In this review, we focus on P2Y receptors and more specifically on P2RY12 that is involved in microglial motility and migration, the first step of neuroinflammation process. We describe the purinergic receptor families, P2RY12 structure, expression and physiological functions. The pharmacological and genetic tools for studying this receptor are detailed thereafter. Last but not least, we report the contribution of microglial P2RY12 to neuroinflammation in acute and chronic brain pathologies in order to better understand P2RY12 microglial role.

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Figures

Figure 1 Schematic secondary structure of P2RY12. P2RY12 is composed of seven α-transmembrane domains connected by three extra- and intracellular loops. There are four extracellular cysteines (Cys) at positions 17, 97, 175, and 270 that form two disulfide bonds.
Figure 1 Schematic secondary structure of P2RY12. P2RY12 is composed of seven α-transmembrane domains connected by three extra- and intracellular loops. There are four extracellular cysteines (Cys) at positions 17, 97, 175, and 270 that form two disulfide bonds.CC BY · PubMed Central
Figure 2 Purinergic receptors and microglial activation states (modified from [37]). In response to ATP release from damaged cells, P2RY12 stimulation triggers the extension of microglial processes towards the site of injury, in cooperation with the adenosine receptor (AR) A3. Both these receptors are upregulated during this step. Then, P2RY12 downregulation and ARA2A upregulation induce the retractation of these processes. Microglial migratory activity also depends on the interaction between P2RY12 and P2RX4. After total retraction of processes, microglia adopt an amoeboid morphology, and exert phagocytosis, pinocytosis or secretory activity depending on the receptor involved. ↑: upregulation or increased activation; ↓: downregulation or reduced activation.
Figure 2 Purinergic receptors and microglial activation states (modified from [37]). In response to ATP release from damaged cells, P2RY12 stimulation triggers the extension of microglial processes towards the site of injury, in cooperation with the adenosine receptor (AR) A3. Both these receptors are upregulated during this step. Then, P2RY12 downregulation and ARA2A upregulation induce the retractation of these processes. Microglial migratory activity also depends on the interaction between P2RY12 and P2RX4. After total retraction of processes, microglia adopt an amoeboid morphology, and exert phagocytosis, pinocytosis or secretory activity depending on the receptor involved. ↑: upregulation or increased activation; ↓: downregulation or reduced activation.CC BY · PubMed Central
Figure 3 Major signal pathways involved in microglial motility and migration after P2RY12 activation. (1) Once released from Gαi, Gβγ activates adenylate cyclase (AC), which induces cyclic adenosine monophosphate (cAMP) increase, phosphorylation of vasodilator-stimulated phosphoprotein (VASP) by protein kinase A (PKA), and then membrane ruffle formation and chemotaxis via the regulation of focal adhesion formation/maturation. (2) The recruitment of β-arrestin recruits and activates extracellular signal-regulated kinase (ERK) 1/2, inducing paxillin phosphorylation which is necessary for adhesion disassembly during chemotaxis. (3) The activation of Src through Gαi triggers the phosphorylation of paxillin, which is essential to focal adhesion assembly. (4) Gαi and Gβγ activate phosphoinositide 3-kinase (PI3K), promoting Akt (=protein kinase B) and Rac activation that are both involved in F-actin polymerization. (5) P2RY12 activation potentiates the activity of TWIK-related halothane-inhibited K+ channel (THIK-1) involved in microglial ramification regulation and surveillance of healthy brain.
Figure 3 Major signal pathways involved in microglial motility and migration after P2RY12 activation. (1) Once released from Gαi, Gβγ activates adenylate cyclase (AC), which induces cyclic adenosine monophosphate (cAMP) increase, phosphorylation of vasodilator-stimulated phosphoprotein (VASP) by protein kinase A (PKA), and then membrane ruffle formation and chemotaxis via the regulation of focal adhesion formation/maturation. (2) The recruitment of β-arrestin recruits and activates extracellular signal-regulated kinase (ERK) 1/2, inducing paxillin phosphorylation which is necessary for adhesion disassembly during chemotaxis. (3) The activation of Src through Gαi triggers the phosphorylation of paxillin, which is essential to focal adhesion assembly. (4) Gαi and Gβγ activate phosphoinositide 3-kinase (PI3K), promoting Akt (=protein kinase B) and Rac activation that are both involved in F-actin polymerization. (5) P2RY12 activation potentiates the activity of TWIK-related halothane-inhibited K+ channel (THIK-1) involved in microglial ramification regulation and surveillance of healthy brain.CC BY · PubMed Central

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Metadata

Authors
Gómez Morillas, A., Besson, V. C., & Lerouet, D.
Affiliations
  • UMR-S1144–Optimisation Thérapeutique en Neuropsychopharmacologie (OTeN), Faculté de Pharmacie de Paris, 4 Avenue de l’Observatoire, Université de Paris, 75006 Paris, France
  • Université Paris Cité (FR)
Corresponding author
Lerouet, Dominique
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2021-02-06
Volume
22
Issue
4
Pages
1636
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms22041636
PMC
PMC7915979
OpenAlex
W3126430294
Cited by
214
References
96
Citations by year
2026: 36 · 2025: 50 · 2024: 72 · 2023: 32 · 2022: 18 · 2021: 6
FWCI
5.93
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Fondation des Gueules Cassées
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
Keywords
microglia, neuroinflammation, P2Y12 receptor, P2Y receptors, purinergic receptors, microglial motility, microglial migration, pharmacological tools, genetic instruments
MeSH terms
Brain, Brain Diseases, Cell Movement, Humans, Inflammation, Lymphocyte Activation, Signal Transduction, Microglia, Receptors, Purinergic P2Y12

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