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HORMONES AND SIGNALING

P2Y5 is a G_i, G_12/13 G protein-coupled receptor activated by lysophosphatidic acid that reduces intestinal cell adhesion

¹Department of Nutritional Science and Toxicology, University of California at Berkeley, Berkeley, California; and ²College of Natural Resources Biological Imaging Facility, University of California at Berkeley, Berkeley, California

Submitted May 21, 2009 ; accepted in final form August 6, 2009

P2Y5 is a G protein-coupled receptor that binds and is activated by lysophosphatidic acid (LPA). We determined that P2Y5 transcript is expressed along the intestinal mucosa and investigated the intracellular pathways induced by P2Y5 activation, which could contribute to LPA effects on intestinal cell adhesion. P2Y5 heterologously expressed in CHO and small intestinal hBRIE 380i cells was activated by LPA resulting in an increase in intracellular calcium ([Ca²⁺]_i) when the cells concurrently expressed G_6qi5myr. P2Y5 activation also increased the phosphorylation of ERK1/2 that was sensitive to pertussis toxin. Together these indicate that P2Y5 activation by LPA induces an increase in [Ca²⁺]_i and ERK1/2 phosphorylation through G_i. We discovered that P2Y5 was activated by farnesyl pyrophosphate (FPP) without a detectable change in [Ca²⁺]_i. The activation of P2Y5 by LPA or FPP induced the activity of a serum response element (SRE)-linked luciferase reporter that was inhibited by the RGS domain of p115RhoGEF, C3 exotoxin, and Y-27632, suggesting the involvement of G_12/13, Rho GTPase, and ROCK, respectively. However, only LPA-mediated induction of SRE reporter activity was sensitive to inhibitors targeting p38 MAPK, PI3K, PLC, and PKC. In addition, only LPA transactivated the epidermal growth factor receptor, leading to an induction of ERK1/2 phosphorylation. These observations correlate with our subsequent finding that P2Y5 activation by LPA, and not FPP, reduced intestinal cell adhesion. This study elucidates a mechanism whereby LPA can act as a luminal and/or serosal cue to alter mucosal integrity.

farnesyl pyrophosphate; GPCR; serum response element; Rho; mucosa