A molecular network that produces spontaneous oscillations in excitable cells of Dictyostelium.
A network of interacting proteins has been found that can account for the spontaneous oscillations in adenylyl cyclase activity that are observed in homogenous populations of Dictyostelium cells 4 h after the initiation of development. Previous biochemical assays have shown that when extracellular adenosine 3',5'-cyclic monophosphate (cAMP) binds to the surface receptor CAR1, adenylyl cyclase and the MAP kinase ERK2 are transiently activated. A rise in the internal concentration of cAMP activates protein kinase A such that it inhibits ERK2 and leads to a loss-of-ligand binding by CAR1. ERK2 phosphorylates the cAMP phosphodiesterase REG A that reduces the internal concentration of cAMP. A secreted phosphodiesterase reduces external cAMP concentrations between pulses. Numerical solutions to a series of nonlinear differential equations describing these activities faithfully account for the observed periodic changes in cAMP. The activity of each of the components is necessary for the network to generate oscillatory behavior; however, the model is robust in that 25-fold changes in the kinetic constants linking the activities have only minor effects on the predicted frequency. Moreover, constant high levels of external cAMP lead to attenuation, whereas a brief pulse of cAMP can advance or delay the phase such that interacting cells become entrained.
Laub
M T
MT
Center for Molecular Genetics, Department of Biology, University of California, San Diego, La Jolla, California 92093, USA.
Loomis
W F
WF
D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000204:Activity Cycles; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002633:Chemotaxis / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004023:Dictyostelium / Q000166:cytology / Q000254:growth & development / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1; D008954:Models, Biological; D009991:Oscillometry; D010507:Periodicity; D015800:Protozoan Proteins / Q000378:metabolism; D011953:Receptors, Cyclic AMP / Q000378:metabolism
D015800:Protozoan Proteins; D011953:Receptors, Cyclic AMP; C068125:cyclic AMP receptor cAR1; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C112742:regA protein, Dictyostelium; D000262:Adenylyl Cyclases