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Vol. 63, Issue 5, 1190-1197, May 2003
Departments of Medicine and Pharmacology and the Cystic Fibrosis
Center, University of North Carolina School of Medicine, Chapel Hill,
North Carolina
Identification of a G protein-coupled receptor activated by UDP-glucose
led us to develop a sensitive and specific assay for UDP-glucose mass
and to test whether this sugar nucleotide is released as an
extracellular signaling molecule. Mechanical stimulation of 1321N1
human astrocytoma cells by a change of medium resulted in an increase
in extracellular levels of both ATP and UDP-glucose. Whereas ATP levels
peaked within 10 min and subsequently returned to resting extracellular
levels of 3 nM, UDP-glucose levels attained a steady state that
exceeded that of resting ATP levels by 3- to 5-fold for at least 3 h. Similar rates of basal release of UDP-glucose and ATP (72 and 81 fmol/min/106 cells) combined with a rate of UDP-glucose
metabolism approximately three times lower than ATP hydrolysis account
for the elevated extracellular UDP-glucose levels on resting cells. A
medium change also resulted in rapid appearance of UDP-glucose on the
luminal surface of highly differentiated polarized human airway
epithelial cells but at levels 2- to 3-fold lower than ATP. However,
nucleotide sugar levels increased 3- to 5-fold over the ensuing 2 h, whereas ATP levels decayed to a resting level; consequently, resting
extracellular UDP-glucose levels exceeded those of ATP by 5- to
10-fold. UDP-glucose also was observed at levels that equaled or
exceeded those of ATP in the extracellular medium of Calu-3 airway
epithelial, COS-7, CHO-K1, and C6 glioma cells. Consistent with the
observation of significant extracellular UDP-glucose levels, expression
of the UDP-glucose-activated P2Y14 receptor in COS-7 cells
resulted in G protein-promoted inositol phosphate accumulation that was
partially reversed by enzymatic removal of UDP-glucose from the medium. Taken together, these results indicate constitutive release of UDP-glucose from physiologically relevant tissues and suggest that
UDP-glucose acts as an autocrine activator of the P2Y14
receptor. Because cellular UDP-glucose is concentrated in the lumen of
the endoplasmic reticulum, we speculate that UDP-glucose release may occur as a result of vesicle transport during trafficking of
glycoproteins to the plasma membrane.
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