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Biophys J, February 2002, p. 582-590, Vol. 82, No. 2
Department of Medical Biochemistry, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom
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+ (K1/2 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.
Biophys J, February 2002, p. 582-590, Vol. 82, No. 2
© 2002 by the Biophysical Society 0006-3495/02/02/582/09 $2.00
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