UDP-Sugars as Extracellular Signaling Molecules: Cellular and Physiologic Consequences of P2Y14 Receptor Activation

Abstract

UDP-sugars, which are indispensable for protein glycosylation reactions in cellular secretory pathways, also act as important extracellular signaling molecules. We discuss here the broadly expressed P2Y14 receptor, a G-protein-coupled receptor targeted by UDP sugars, and the increasingly diverse set of physiologic responses discovered recently functioning downstream of this receptor in many epithelia as well as in immune, inflammatory, and other cells.

Graphical abstract

Fig. 1.

Pathways for UDP-sugar release. UDP-glucose (UDPG) and other UDP-sugars are synthesized in the cytosol and enter the secretory pathway via ER/Golgi-resident SLC35 transporters, using UMP as antiporter substrates. ER/Golgi UDP-sugars are used for glycosylation, yielding UDP as a reaction product, and UDP is metabolized to UMP. (i) Residual UDP-sugars in the ER/Golgi lumen are released as cargo via the constitutive secretory pathway. (ii) Unlike ATP and UTP, UDP-sugars are not predicted to be substrates of the vesicular nucleotide transporter (VNUT), but Golgi-derived vesicles are a source of UDP-sugars in specialized granules susceptible to Ca²⁺-regulated exocytosis. Not shown: Golgi UDP is released with UDP-sugars. Whether pannexin 1 mediates the release of cytosolic UDP-sugars is not known. PPi, pyrophosphate; G-1P, glucose-1P.

Fig. 2.

Signaling pathways associated with P2Y₁₄R activation. The P2Y₁₄R couples to G_i, thus promoting Gα_i- and Gβγ-mediated inhibition of adenylyl cyclases 1, 3, 5, 6, 8, and 9. Additional direct and indirect effectors of Gβγ include K⁺ channels (GIRK), phosphatidylinositol 3-kinase-γ, GPCR kinase 2 and 3, and phospholipase C β2 and β3, P-rex1 Rac GEF, and SNAP-25. Rho, MAPKs, and potentially other effectors not listed represent examples of signaling proteins that are also activated downstream of Gβγ.