. 2021 Aug 2;19(1):163–172. doi: 10.1007/s11302-021-09801-x

Table 3.

The mechanism of depression and chronic pain comorbidity mediated by P2YRs

P2Y receptor subtype	Molecular mechanism	Method/experimental models	Type of disease	Treatment
P2Y1R, P2Y2R, P2Y4R, P2Y11R	Coupled with Gq/G11 to activate the PLC/IP3/Ca²⁺ signaling pathway [52]	P2Y1 knockout mice [52]	Depression and chronic pain	-
P2Y11R	Coupled with Gs, mobilizes Ca²⁺ in the inositol 1,4,5-trisphosphate-sensitive reservoir, and activates Ca²⁺/CaM kinase, leading to cAMP accumulation and PKA activation [18, 56]	Astrocyte-selective VNUT-knockout mice [18], symptomatic/end stage SOD1-G93A ALS mice [56]	Depression	-
P2Y12R, P2Y13R, and P2Y14R	Coupled with Gi/Go and inhibits the synthesis of adenylate cyclase and cAMP [52]	Immunohistochemical analysis, ratio metric calcium imaging [52]	Reduce chronic pain	-
P2Y6R, P2Y12R	Activates the phagocytic function of microglia, induces microglial chemotaxis, and is associated with chronic pain [57]	-	Chronic pain	-

Abbreviations: P2Y1R, P2Y1 receptor; PLC, phospholipase C; CaM kinase, calmodulin-dependent kinase; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; VNUT, vesicular nucleotide transporter; ALS, amyotrophic lateral sclerosis