Kinetics on Demand Is a Simple Mathematical Solution that Fits Recorded Caffeine-Induced Luminal SR Ca(2+) Changes in Smooth Muscle Cells

The process of Ca(2+) release from sarcoplasmic reticulum (SR) comprises 4 phases in smooth muscle cells. Phase 1 is characterized by a large increase of the intracellular Ca(2+) concentration ([Ca(2+)](i)) with a minimal reduction of the free luminal SR [Ca(2+)] ([Ca(2+)](FSR)). Importantly, active SR Ca(2+) ATPases (SERCA pumps) are necessary for phase 1 to occur. This situation cannot be explained by the standard kinetics that involves a fixed amount of luminal Ca(2+) binding sites. A new mathematical model was developed that assumes an increasing SR Ca(2+) buffering capacity in response to an increase of the luminal SR [Ca(2+)] that is called Kinetics-on-Demand (KonD) model. This approach can explain both phase 1 and the refractory period associated with a recovered [Ca(2+)](FSR). Additionally, our data suggest that active SERCA pumps are a requisite for KonD to be functional; otherwise luminal SR Ca(2+) binding proteins switch to standard kinetics. The importance of KonD Ca(2+) binding properties is twofold: a more efficient Ca(2+) release process and that [Ca(2+)](FSR) and Ca(2+)-bound to SR proteins ([Ca(2+)](BSR)) can be regulated separately allowing for Ca(2+) release to occur (provided by Ca(2+)-bound to luminal Ca(2+) binding proteins) without an initial reduction of the [Ca(2+)](FSR).