Refractory [Ca²⁺]_i response to the application of caffeine.

<p>A set of experimental results (blue line) of simultaneous recording of [Ca²⁺]_i (upper trace) and SR Ca²⁺ levels (bottom trace) in response to the application of two pulses of caffeine (middle trace) are presented. Notice that by 30 s after the first application of caffeine both [Ca²⁺]_i and SR Ca²⁺ levels have recovered to resting levels. A second application of caffeine produce the same response in the SR Ca²⁺ with minimal effect on the [Ca²⁺]_i. The numerical simulations of KonD model (red line) and SK model (green line) are also shown. The simulation for both models was calculated by solving numerically the differential equations with the parameters shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0138195#pone.0138195.t001" target="_blank">Table 1</a> for 20mM of caffeine with parameter gamma equals to 2.54%. Changing parameter gamma helps SK model to fit the caffeine-induced [Ca²⁺]_i transient but does not show the same time course for the recovery of the [Ca²⁺]_FSR (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0138195#pone.0138195.s004" target="_blank">S4 Fig</a>).