A Buffering SERCA Pump in Models of Calcium Dynamics

Abstract

Many cells use oscillations in calcium concentration to transmit messages. The oscillations largely result from an influx of calcium into the cytosol from the endoplasmic reticulum (ER), followed by an efflux of calcium from the cytosol back into the ER. The sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) pump pumps calcium into the ER. It binds calcium on the cytosolic side and releases it on the ER side and in the delay between binding and release, calcium is buffered by the pump. We developed a model of a buffering SERCA pump and investigated whether including this in a model of calcium oscillations has any significant effects. We found that the oscillations produced when using the SERCA pump, which does not buffer calcium, have a larger amplitude and a slightly smaller period than when using the buffering SERCA pump. We show that the buffering SERCA pump shows adaptation to a stimulus, and we demonstrate that, by using a bidirectional SERCA pump, we are able to eliminate futile cycling of calcium between the cytosol and ER when the cell is at rest.

Modelling sarcoplasmic reticulum calcium ATPase and its regulation in cardiac myocytes

“…During recent years, complex kinetic SERCA models, which include the binding and release of calcium and the change of conformation powered by ATP, have been presented. Among these schemes are, for example, descriptions with two (Matsuoka et al 2003;Higgins et al 2006), four (MacLennan et al 1997;Matsuoka et al 2003;Higgins et al 2006) and six transitional states (Dode et al 2002;Stokes & Green 2003;Yano et al 2004; figure 2), corresponding to various conformational states during the transport cycle.…”

“…From a purely modelling perspective, the four-state model is problematic due to the number of unknown parameter values. Higgins et al (2006) 2C ions to the SERCA pump from the cytoplasm, phosphorylation of the pump by ATP, conversion from the E 1 (cytosolic high-affinity binding site) into the E 2 (luminal low-affinity binding site) conformation state, translocation of Ca 2C from the cytosol to the luminal side of the SR membrane, release of Ca 2C into the SR, dephosphorylation of the pump and conversion from the E 2 into the E 1 conformation state. dilemma by presenting a reduced, two-state model, for which they were able to assign parameter values based on thermodynamic calculations.…”

Translating Intracellular Calcium Signaling into Models

“…However, experimental measurements strongly suggest that firstly luminal Ca 2+ feeds back to SERCA pump dynamics and secondly Ca 2+ movement between the cytosol and the ER/SR proceeds along multiple distinct states of the SERCA pump molecule. These experimental results have led to more comprehensive models of SERCA pumps such as in (Sneyd et al 2003;Shannon et al 2004;Higgins et al 2006;Koivumäki et al 2009;Tran et al 2009) The advantage of compartmentalized models lies in the computational ease in accounting for largely varying Ca 2+ concentrations and spatial gradients. A single point model cannot incorporate the different peak values and time courses of e.g.…”

Modelling calcium microdomains using homogenisation

“…Higgins et al [12] have used a four state model of the SERCA pump, and have investigated the effect of including the buffering effect of the pump, in a compartmental model of a non-excitable cell. When the pump transports calcium ions between the cytosol and the SR/ER, some of the ions are bound to the pump protein.…”

“…They are neither in the cytosol or the SR/ER, so are being buffered by the pump. Higgins et al [12] found that the buffering SERCA pump slowed calcium oscillations and significantly reduced their amplitude. Here we have included the same buffering SERCA pump in our three-dimensional model of a half-sarcomere in a cardiac cell.…”