title: Phosphoinositide 3-kinase activity controls the chemoattractant-mediated activation and adaptation of adenylyl cyclase.
abstract: The binding of chemoattractants to cognate G protein-coupled receptors activates a variety of signaling cascades that provide spatial and temporal cues required for chemotaxis. When subjected to uniform stimulation, these responses are transient, showing an initial peak of activation followed by a period of adaptation, in which activity subsides even in the presence of stimulus. A tightly regulated balance between receptor-mediated stimulatory and inhibitory pathways controls the kinetics of activation and subsequent adaptation. In Dictyostelium, the adenylyl cyclase expressed during aggregation (ACA), which synthesizes the chemoattractant cAMP, is essential to relay the signal to neighboring cells. Here, we report that cells lacking phosphoinositide 3-kinase (PI3K) activity are deficient in signal relay. In LY294002-treated cells, this defect is because of a loss of ACA activation. In contrast, in cells lacking PI3K1 and PI3K2, the signal relay defect is because of a loss of ACA adaptation. We propose that the residual low level of 3-phosphoinositides in pi3k(1-/2-) cells is sufficient to generate the initial peak of ACA activity, yet is insufficient to sustain the inhibitory phase required for its adaptation. Thus, PI3K activity is poised to regulate both ACA activation and adaptation, thereby providing a link to ensure the proper balance of counteracting signals required to maintain optimal chemoresponsiveness.
authors.affiliation: Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4256, USA.
authors.forename: Frank I
authors.initials: FI
authors.lastname: Comer
authors.forename: Carole A
authors.initials: CA
authors.lastname: Parent
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002630:Chemotactic Factors / Q000494:pharmacology*; D004023:Dictyostelium / Q000187:drug effects / Q000201:enzymology; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D021381:Protein Transport; D015398:Signal Transduction
chemical_list: D000262:Adenylyl Cyclases; D002630:Chemotactic Factors; D019204:GTP-Binding Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors