Peercy Bradford E, Sherman Arthur S, Bertram Richard
Department of Mathematics and Statistics, University of Maryland, Baltimore County, Baltimore, Maryland.
Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
Biophys J. 2015 Jul 21;109(2):439-49. doi: 10.1016/j.bpj.2015.06.024.
Recent advances in imaging technology have revealed oscillations of cyclic adenosine monophosphate (cAMP) in insulin-secreting cells. These oscillations may be in phase with cytosolic calcium oscillations or out of phase. cAMP oscillations have previously been modeled as driven by oscillations in calcium, based on the known dependence of the enzymes that generate cAMP (adenylyl cyclase) and degrade it (phosphodiesterase). However, cAMP oscillations have also been reported to occur in the absence of calcium oscillations. Motivated by similarities between the properties of cAMP and metabolic oscillations in pancreatic β cells, we propose here that in addition to direct control by calcium, cAMP is controlled by metabolism. Specifically, we hypothesize that AMP inhibits adenylyl cyclase. We incorporate this hypothesis into the dual oscillator model for β cells, in which metabolic (glycolytic) oscillations cooperate with modulation of ion channels and metabolism by calcium. We show that the combination of oscillations in AMP and calcium in the dual oscillator model can account for the diverse oscillatory patterns that have been observed, as well as for experimental perturbations of those patterns. Predictions to further test the model are provided.
成像技术的最新进展揭示了胰岛素分泌细胞中环磷酸腺苷（cAMP）的振荡。这些振荡可能与细胞质钙振荡同相或异相。基于生成cAMP的酶（腺苷酸环化酶）和降解它的酶（磷酸二酯酶）的已知依赖性，cAMP振荡以前被建模为由钙振荡驱动。然而，也有报道称在没有钙振荡的情况下会发生cAMP振荡。受胰腺β细胞中cAMP特性与代谢振荡之间相似性的启发，我们在此提出，除了受钙的直接控制外，cAMP还受代谢的控制。具体而言，我们假设AMP抑制腺苷酸环化酶。我们将这一假设纳入β细胞的双振荡器模型，其中代谢（糖酵解）振荡与钙对离子通道和代谢的调节相互作用。我们表明，双振荡器模型中AMP和钙的振荡组合可以解释所观察到的各种振荡模式，以及这些模式的实验扰动。还提供了进一步测试该模型的预测。
