Kang Minchul, Othmer Hans G
Department of Molecular Physiology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Phys Biol. 2007 Dec 13;4(4):325-43. doi: 10.1088/1478-3975/4/4/009.
A model of ligand-induced intracellular calcium (Ca2+) responses incorporating phospholipase C (PLC) and protein kinase C (PKC) is developed for the purpose of understanding the mechanisms underlying the observed temporal patterns of intracellular calcium (Ca(i)2+) under sustained agonist stimulation. Some studies have suggested that inhibition of ligand receptors and PLC by PKC could generate sinusoidal Ca2+ oscillations, while PKC-independent Ca2+-induced Ca2+ release (CICR) via IP(3)-gated Ca2+ channels on the endoplasmic reticulum (ER) is believed to be responsible for baseline spiking. However, some evidence also indicates that baseline spiking can be observed under high-PKC activity, or under low-PKC activity with low agonist stimulus, as well. Insight into the basis of these observations regarding the role of PKC in Ca(i)2+ response patterns can be gained by developing and analyzing a mathematical model of Ca(i)2+ responses. We do this herein and find that (1) interaction of CICR and the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) pump is enough to generate both types of Ca(i)2+ oscillations, (2) there exist four possible Ca(i)2+ response patterns under sustained agonist stimulus: a sub-threshold response (SR), baseline spiking, sinusoidal oscillations (SO) and transient with plateau, and (3) the IP(3) concentration, which is controlled by the strength of the interaction between PKC and PLC, can be used to predict the Ca(i)2+ response patterns. From this analysis we conclude that the different patterns of Ca(i)2+ oscillations can be understood as a generic consequence of the interactions between CICR via the IP(3)-gated Ca(2+) channels in response to changes in the level of IP(3), and re-uptake into the ER/SR via the SERCA pump. PKC, in conjunction with PLC, can act as a switch between different Ca(i)2+ response patterns by modulating the cytosolic IP(3) level, which determines the Ca(i)2+ patterns.
为了理解在持续激动剂刺激下细胞内钙（Ca(i)2+）观察到的时间模式背后的机制，开发了一个包含磷脂酶C（PLC）和蛋白激酶C（PKC）的配体诱导细胞内钙（Ca2+）反应模型。一些研究表明，PKC对配体受体和PLC的抑制可产生正弦波状的Ca2+振荡，而通过内质网（ER）上IP(3)门控Ca2+通道的PKC非依赖性Ca2+诱导Ca2+释放（CICR）被认为是基线尖峰的原因。然而，一些证据还表明，在高PKC活性下，或在低激动剂刺激的低PKC活性下，也可观察到基线尖峰。通过开发和分析Ca(i)2+反应的数学模型，可以深入了解这些关于PKC在Ca(i)2+反应模式中作用的观察结果的基础。我们在此进行了此项研究，发现：（1）CICR与肌浆网/内质网钙ATP酶（SERCA）泵的相互作用足以产生两种类型的Ca(i)2+振荡；（2）在持续激动剂刺激下存在四种可能的Ca(i)2+反应模式：阈下反应（SR）、基线尖峰、正弦波振荡（SO）和伴有平台期的瞬态反应；（3）由PKC与PLC之间相互作用强度控制的IP(3)浓度可用于预测Ca(i)2+反应模式。从该分析中我们得出结论，Ca(i)2+振荡的不同模式可理解为通过IP(3)门控Ca(2+)通道的CICR响应IP(3)水平变化与通过SERCA泵重新摄取到ER/SR之间相互作用的一般结果。PKC与PLC一起，可通过调节胞质IP(3)水平来充当不同Ca(i)2+反应模式之间的开关，而IP(3)水平决定了Ca(i)2+模式。
