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J Biol Chem, Vol. 273, Issue 14, 8161-8168, April 3, 1998

Cell Density Sensing Mediated by a G Protein-coupled Receptor Activating Phospholipase C

From the Howard Hughes Medical Institute, Department of Biochemistry and Cell Biology, MS-140, Rice University, Houston, Texas 77005-1892

When the unicellular eukaryote Dictyostelium discoideum starves, it senses the local density of other starving cells by simultaneously secreting and sensing a glycoprotein called conditioned medium factor (CMF). When the density of starving cells is high, the corresponding high density of CMF permits signal transduction through cAR1, the chemoattractant cAMP receptor. cAR1 activates a heterotrimeric G protein whose -subunit is G2. CMF regulates cAMP signal transduction in part by regulating the lifetime of the cAMP-stimulated G2-GTP configuration. We find here that guanosine 5'-3-O-(thio)triphosphate (GTPS) inhibits the binding of CMF to membranes, suggesting that the putative CMF receptor is coupled to a G protein. Cells lacking G1 (G1 null) do not exhibit GTPS inhibition of CMF binding and do not exhibit CMF regulation of cAMP signal transduction, suggesting that the putative CMF receptor interacts with G1. Work by others has suggested that G1 inhibits phospholipase C (PLC), yet when cells lacking either G1 or PLC were starved at high cell densities (and thus in the presence of CMF), they developed normally and had normal cAMP signal transduction. We find that CMF activates PLC. G1 null cells starved in the absence or presence of CMF behave in a manner similar to control cells starved in the presence of CMF in that they extend pseudopods, have an activated PLC, have a low cAMP-stimulated GTPase, permit cAMP signal transduction, and aggregate. Cells lacking G have a low PLC activity that cannot be stimulated by CMF. Cells lacking PLC exhibit IP₃ levels and cAMP-stimulated GTP hydrolysis rates intermediate to what is observed in wild-type cells starved in the absence or in the presence of an optimal amount of CMF. We hypothesize that CMF binds to its receptor, releasing G from G1. This activates PLC, which causes the G2 GTPase to be inhibited, prolonging the lifetime of the cAMP-activated G2-GTP configuration. This, in turn, allows cAR1-mediated cAMP signal transduction to take place.

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