Abstract
The process of Ca2+ release from sarcoplasmic reticulum (SR) comprises 4 phases in smooth muscle cells. Phase 1 is characterized by a large increase of the intracellular Ca2+ concentration ([Ca2+]i) with a minimal reduction of the free luminal SR [Ca2+] ([Ca2+]FSR). Importantly, active SR Ca2+ 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 Ca2+ binding sites. A new mathematical model was developed that assumes an increasing SR Ca2+ buffering capacity in response to an increase of the luminal SR [Ca2+] that is called Kinetics-on-Demand (KonD) model. This approach can explain both phase 1 and the refractory period associated with a recovered [Ca2+]FSR. Additionally, our data suggest that active SERCA pumps are a requisite for KonD to be functional; otherwise luminal SR Ca2+ binding proteins switch to standard kinetics. The importance of KonD Ca2+ binding properties is twofold: a more efficient Ca2+ release process and that [Ca2+]FSR and Ca2+-bound to SR proteins ([Ca2+]BSR) can be regulated separately allowing for Ca2+ release to occur (provided by Ca2+-bound to luminal Ca2+ binding proteins) without an initial reduction of the [Ca2+]FSR.
Highlights
The main internal Ca2+ store is the sarcoplasmic reticulum (SR) in muscle cells and the endoplasmic reticulum (ER) in non-muscle cells
Simultaneous recordings of [Ca2+]i and [Ca2+]FSR in smooth muscle cells have demonstrated that activation of RyRs by caffeine induces a large increase in [Ca2+]i before any reduction of the [Ca2+]FSR, which is followed by a large reduction of [Ca2+]FSR and a plateau of the [Ca2+]i increase
To get an insight on how SERCA pumps might control SR Ca2+ release in smooth muscle cells we have developed a simple deterministic mathematical model based on the [Ca2+]i response to two different caffeine concentrations (2 and 20 mM) and the effect of rapid inhibition of SERCA pump with thapsigargin on the 20 mM caffeine-induced [Ca2+]i response
Summary
The main internal Ca2+ store is the sarcoplasmic reticulum (SR) in muscle cells and the endoplasmic reticulum (ER) in non-muscle cells These membrane organelles are distributed throughout the cell and are endowed with three main elements 1) SERCA pumps, 2) different types of Ca2+ release channels [Ryanodine or inositol 1,4,5-trisphosphate receptors (RyRs and IP3Rs, respectively)], and 3) luminal Ca2+-binding proteins (calsequestrin or calreticulin). All these different types of proteins produce and modulate Ca2+ release events that can be either localized in nature or traveling Ca2+ waves [1].
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