Coupling of P2Y receptors to G proteins and other signaling pathways

Abstract

P2Y receptors are G protein-coupled receptors (GPCRs) that are activated by adenine and uridine nucleotides and nucleotide sugars. There are eight subtypes of P2Y receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14), which activate intracellular signaling cascades to regulate a variety of cellular processes, including proliferation, differentiation, phagocytosis, secretion, nociception, cell adhesion, and cell migration. These signaling cascades operate mainly by the sequential activation or deactivation of heterotrimeric and monomeric G proteins, phospholipases, adenylyl and guanylyl cyclases, protein kinases, and phosphodiesterases. In addition, there are numerous ion channels, cell adhesion molecules, and receptor tyrosine kinases that are modulated by P2Y receptors and operate to transmit an extracellular signal to an intracellular response.

Loss of P2Y2 Nucleotide Receptors Enhances Early Pathology in the TgCRND8 Mouse Model of Alzheimer's Disease

“…In particular, the G q protein-coupled P2Y 2 receptor (P2Y 2 R) that is activated equipotently by ATP or UTP [14–16] has been identified as a modulator of neuroinflammatory processes, including those relevant to AD pathology [17–19]. Upregulation of P2Y 2 Rs under inflammatory conditions occur in a variety of tissues and cells [20–23], including brain cells [24, 25], whereupon activation by ATP or UTP stimulates growth factor receptors, integrins and cytoskeletal proteins via unique structural motifs in the P2Y 2 R that enable access to signaling pathways beyond the G q protein [26]. In rat primary cortical neurons, P2Y 2 Rs are upregulated following treatment with interleukin-1β (IL-1β) [24], a cytokine shown to be elevated in AD patients [27, 28].…”

Low-affinity binding incisto P2Y2R mediates force-dependent integrin activation during hantavirus infection

“…, 2005; Liao et al. , 2007; Erb and Weisman, 2012). 1321N1 cells are devoid of β 3 integrin subunits and are not permissive to productive SNV infection in our hands.…”

“…, 2005; Liao et al. , 2007; Erb and Weisman, 2012). The authors then showed that the presumptive RGD P2Y 2 R- integrin engagement conferred to the G q PCR the ability to activate the heterotrimeric G-protein Gα 12 , which stimulated RhoA signaling (Liao et al.…”

Biochemical and molecular characterisation of the proposed P2Y1-P2Y12 receptor heterodimer in tsA201 cells

“…P2Y1, P2Y2, P2Y4, P2Y6 and P2Y11 receptors mainly couple to Gq/11 α subunits, whilst P2Y12, P2Y13 and P2Y14 receptors couple to Gi/o; the P2Y11 and Weisman, 2012).…”

“…The released βγ complex can also modulate its own targets, including ion channels such as N-type Ca 2+ channels (Simon et al, 2002), and PLCβ to invoke IP3 based signalling in Gi/o coupled receptors (Murthy and Makhlouf, 1998). Along with these typical second messenger actions, P2Y receptors are able to mediate cellular activities through other pathways (reviewed in Erb and Weisman, 2012). For example Gq/11 subunits additionally bind to and stimulate the p63RhoGEF guanine nucleotide exchange factor, which can then act on downstream Rho targets (Lutz et al, 2005).…”