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Modeling the effects of reactive oxygen species on the store-operated calcium entry.

The aim of this paper is to develop an integrative, qualitative, phenomenological, and mathematical model for the interplay between calcium and reactive oxygen species (ROS) in the subsystem of the store-operated calcium entry (SOCE). Experimental observations indicate that ROS inhibits the sarcoplasmic or endoplasmic reticulum (ER) calcium-ATPases (SERCA) and the calcium release-activated calcium (CRAC) channels, and stimulates IP3 receptors in a biphasic manner. Based on these observations, we developed a mathematical model in which a biphasic function is used to model the biphasic ROS effect. Then the model is tested by using several experimental data, showing that the model simulations agree qualitatively with the experimental observations. After the testing, seven qualitative and phenomenological predictions are drawn from the model: (1) The SOCE peak, the steady cytosolic and ER calcium, the CRAC channel opening might exhibit a triphasic pattern as the ROS dosage increases: the SOCE peak, the steady cytosolic calcium, and the CRAC channel opening decrease quickly over small ROS dosages, increase quickly over intermediate ROS dosages, and decrease slowly over large ROS dosages while the ER calcium is opposite. The pattern persists under moderate variations of some parameters. (2) The SOCE peak, the CRAC channel opening and the steady cytosolic calcium might be most sensitive to ROS around the lowest intermediate ROS dosage while the steady ER calcium might be most sensitive to ROS around the highest intermediate ROS dosage. (3) The sensitivity index (relative derivative) of the CRAC channel opening to the ER calcium or the cytosolic calcium at equilibrium is always negative for all ROS dosages, telling that the percentage of the CRAC channel opening increases as the ER calcium or the cytosolic calcium decreases, that is, emptying the ER calcium or reducing the cytosolic calcium activates the CRAC channel. (4) The CRAC channel opening might be most sensitive to the ER (cytosolic) calcium at the maximum of the ER (cytosolic) calcium with the lowest (highest) intermediate ROS dosage while the CRAC channel opening might be least sensitive to the ER (cytosolic) calcium at the minimum of the ER (cytosolic) calcium with the highest (lowest) intermediate ROS dosage. (5) The CRAC channel opening might be much more sensitive to the ER calcium than to the cytosolic calcium; (6) The activation of STIM1 by the lower ER calcium might be stronger than the inhibition of STIM1 by ROS; (7) ROS has less impact on high STIM1/Orai1 expression than low STIM1/Orai1 expression. As modeling conclusions, the above mathematical predictions are purely mathematical conjectures before an experimental test is conducted to justify them.

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