Modeling Study On Calcium Oscillations Based On Changes Of SERCA In Pancreatic β-Cells Of Type ⅡDiabetic Rats

Insulin released from pancreaticβ-cells is the only hormone which lowers blood glucose in human body. Both the insufficient and relative lack of insulin secretion( the insulin resistance) lead to the high blood glucose, and then the diabetes. Insulin secretion can not be separated from the triggering of the intracellular calcium (Ca²⁺). Following the extracellular glucose stimulation,β-cells depolarize, and the cytosolic Ca²⁺ concentration increases, thereby triggering the direct interaction between the secreted proteins positioned in the vesicle membrane and that in the plasma membrane, which can promote the fusion of the vesicle membrane and the plasma membrane and lead to insulin secretion. So the increasing Ca²⁺ concentration is the basal condition of insulin secretion from pancreaticβ-cells.In the normal conditions, cytosolic Ca²⁺ concentration is kept at a low concentration level, its alteration is mainly regulated by the calcium channels, the endoplasmic reticulum (ER) and the calcium clearance including plasma membrane Ca²⁺-ATPase (PMCA) pumps, plasma membrane Na+/Ca²⁺exchanger (NCX), sarco-endoplasmic reticulum Ca²⁺-ATPase (SERCA) pumps and the calcium buffers. Usually, the form in which the intracellular calcium modulates the secretion is the different frequency of calcium oscillations? in pancreaticβ-cells, the continuance of calcium oscillations depends on an influx of the extracellular calcium driven by the glucose stimulation. In response to the stimulation, the ratio of ATP to ADP inβ-cells increases, ATP-sensitive K+ channels (KATP) are closed andβ-cells depolarize to activate the voltage-gated calcium channels, followed by calcium influx. At the moment, the ER also releases calcium into the cytosol, leading to the increased cytosolic Ca²⁺ concentration. To keep the cytosolic Ca²⁺ concentration at the resting concentration level, four clearance mechanisms remove calcium from the cytosol. PMCA pumps and SERCA pumps transport calcium against its concentration gradient by using the chemical energy derived from the hydrolysis of ATP, and then the ATP-to-ADP ratio is reduced indirectly, followed by the cytosolic Ca²⁺ concentration decreasing and the plasma membrane repolarizing. Due to glucose stimulation once more, the extracellular calcium flow into the cytosol again, thus there appear the calcium oscillations.The formation of calcium oscillations requires the participation of SERCA pumps. Inβ-cells, when the cytosolic Ca²⁺ concentration is 0.5μmol/L or 0.9μmol/L, the contribution of SERCA pumps to calcium removal accounts for above 60%, so SERCA pumps play an important role in decreasing cytosolic Ca²⁺ concentration to the resting concentration level. SERCA, a typical class of P-type ATPases, has three SERCA genes (SERCA1-3). SERCA2 includes two isoforms SERCA2a and SERCA2b, and the pancreaticβ-cells contain SERCA2b and SERCA3.Recently, it has been shown that the defects of SERCA pumps function in pancreaticβ-cells have been consistently found in both type I and type II diabetes. To quantitatively investigate the correlation of the defects in SERCA pumps function and the alternation of the cytosolic Ca²⁺ concentration in diseasedβ-cells, a biophysical model based on the measurement results of calcium fluorescence was built. In the previous study, the process of SERCA pumps transporting calcium has been usually modeled by a simple Hill equation, which didn't take into account the defects of SERCA pumps in diseasedβ-cells. Therefore a model of SERCA pump in diseasedβ-cells was built based on the original SERCA pump model. The new model replaced the original one to be used in the model of calcium oscillations and the calcium waves of the diseasedβ-cells were obtained. After comparing the calcium waves of the diseasedβ-cells with that of the normalβ-cells, the effect of the defects of SERCA pumps in diseasedβ-cells on cytosolic Ca²⁺ concentration could be analyzed. The result is that the change made cytosolic Ca²⁺ concentration increase, and caused the period and the amplitude of cytosolic calcium oscillations to increase. Furthermore, SERCA pumps transport calcium into the ER by using the energy derived from ATP hydrolysis, which alters not only ATP concentration but also the calcium concentration in the ER. The defects of SERCA pumps will affect both ATP concentration and the calcium concentration in the ER. In this paper, the alterations of both ATP concentration and the calcium concentration in the ER in diseasedβ-cells were also detected by the mathematical modeling. At last, to ATP oscillations, the defects of SERCA pumps led to the decreased cytosolic ATP concentration and the increased period of ATP oscillations, but no significant alteration of the amplitude, and to calcium oscillations in the ER, it made the period of calcium oscillations in the ER increase, but the amplitude decrease.