Microglia and Neuroinflammation: What Place for P2RY12?

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.

Keywords: P2RY12; microglia; neuroinflammation; purinergic receptor.

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 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 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.