The Signaling Pathway of the ADP Receptor P2Y12 in the Immune System: Recent Discoveries and New Challenges

Figures

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  Figure 1. ADP-induced P2Y12 downstream signaling. ADP binds to and activates the ADP receptor P2Y12 leading to the inhibition of adenylate cyclases, a decrease in cAMP, PI3 kinase activation, and an increase in AKT phosphorylation. This signaling pathway eventually leads to platelet activation and aggregation. This figure has been generated using the software Biorender (https://www.biorender.com).

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  Figure 2. Expression of GPCRs and other selected genes in homeostatic microglia and disease-associated microglia (DAM). (A) Single-cell RNA sequencing and clustering of the mRNA expression pattern revealed 14 subpopulations of human microglia cells [58]. These subpopulations are equipped with different subsets of GPCRs and P2Y12 is found in all microglial subpopulations. Significantly expressed GPRCR mRNAs are shown (red = high, blue = low expression, and circle size reflexes the portion of the cells in the cluster expressing the gene). As references, the microglial markers IBA1 (AIF1) and TREM2 are given at the top of the list. (B) The homeostatic (resting) microglia express more than 30 GPCRs, and the receptors with the highest expression are listed. Together with additional genes (e.g., Tmem19, Hexb) these GPCRs are considered marker genes for homeostatic microglia. Transcriptome studies of microglia from patients and mouse models of neurodegenerative diseases revealed changes in the expression of some of these marker transcripts. This information is taken from different RNA sequencing studies [58,59,60,61].

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  Figure 3. A schematic representation of how P2Y12 activation, blockage, and deficiency are altered in inflammatory conditions and a list of which cells appear to be affected. Overall, P2Y12 did appear to be activated in all the inflammatory conditions reported in the graph. However, it is still unclear whether blockage or deficiency could consistently improve the outcome. The arrow pointing top and down represents an increase and decrease respectively. Cells with both arrows shows inconsistency.