Cardiac contraction and relaxation dynamics result from a set of simultaneously
interacting Ca$^2+$ regulatory mechanisms. In this study, cardiocyte
Ca$^2+$ dynamics were modeled using a set of six differential
equations that were based on theories, equations, and parameters
described in previous studies. Among the unique features of the model
was the inclusion of bidirectional modulatory interplay between the
sarcoplasmic reticular Ca$^2+$ release channel (SRRC) and calsequestrin
(CSQ) in the SR lumen, where CSQ acted as a dynamic rather than simple
Ca$^2+$ buffer, and acted as a Ca$^2+$ sensor in the SR lumen
as well. The inclusion of this control mechanism was central in overcoming
a number of assumptions that would otherwise have to be made about
SRRC kinetics, SR Ca$^2+$ release rates, and SR Ca$^2+$ release
termination when the SR lumen is assumed to act as a simple, buffered
Ca$^2+$ sink. The model was sufficient to reproduce a graded
Ca$^2+$-induced Ca$^2+$ release (CICR) response, CICR with
high gain, and a system with reasonable stability. As constructed,
the model successfully replicated the results of several previously
published experiments that dealt with the Ca$^2+$ dependence
of the SRRC (, J. Gen. Physiol. 85:247-289), the refractoriness of
the SRRC (, Am. J. Physiol. 270:C148-C159), the SR Ca$^2+$ load
dependence of SR Ca$^2+$ release (, Am. J. Physiol. 268:C1313-C1329;,
J. Biol. Chem. 267:20850-20856), SR Ca$^2+$ leak (, J. Physiol.
(Lond.). 474:463-471;, Biophys. J. 68:2015-2022), SR Ca$^2+$
load regulation by leak and uptake (, J. Gen. Physiol. 111:491-504),
the effect of Ca$^2+$ trigger duration on SR Ca$^2+$ release
(, Am. J. Physiol. 258:C944-C954), the apparent relationship that
exists between sarcoplasmic and sarcoplasmic reticular calcium concentrations
(, Biophys. J. 73:1524-1531), and a variety of contraction frequency-dependent
alterations in sarcoplasmic Ca$^2+$ dynamics that are normally
observed in the laboratory, including rest potentiation, a negative
frequency-Ca$^2+$ relationship, and extrasystolic potentiation.
Furthermore, under the condition of a simulated Ca$^2+$ overload,
an alternans-like state was produced. In summary, the current model
of cardiocyte Ca$^2+$ dynamics provides an integrated theoretical
framework of fundamental cellular Ca$^2+$ regulatory processes
that is sufficient to predict a broad array of observable experimental
outcomes.