A mathematical model predicts that calreticulin interacts with the endoplasmic reticulum Ca2+-ATPase

A robust mathematical model developed from single cell calcium (Ca2+) dynamics has enabled us to predict the consequences of over-expression of endoplasmic reticulum-located chaperones. Model predictions concluded that calreticulin interacts with the lumenal domain of the sarcoplasmic and endoplasmic reticulum Ca2+-activated ATPase (SERCA) pump, altering pump affinity for Ca2+ (K-1/2 Switches from 247 to 431 nM) and hence generating Ca2+ oscillations. Expression of calreticulin in the ER generated an average of six transient-decline oscillations during the Ca2+ recovery phase, upon exposure to maximal levels of the agonist ATP. In contrast, normal cells produced a single Ca2+, transient with few or no oscillations. By conditioning the model to experimental data, parameters for generation and decay of IP3 and SERCA pump kinetics were determined. To elucidate the possible source of the oscillatory behavior three possible oscillators, 1) IP3, 2) IP3R, and 3) SERCA pump, were investigated and parameters constrained by experimental data to produce the best candidate. Each of the three oscillators generated very good fits with experimental data. However, converting a normal exponential recovery to a transient-decline oscillator predicted that the SERCA pump is the most likely candidate for calreticulin-meditated Ca2+ release, highlighting the role of this chaperone as a signal protein within the endoplasmic reticulum.