A new Mathematical Formulation of the Plasma Membrane Ca 2+-Atpase (PMCA) Provides Stability to Simulated Ca 2+ Signaling in Human T Cells

Abstract

In lymphocytes Ca2+ signals are essential for diverse cellular functions. After antigen binds to the T cell receptor a series of reactions are initiated that generate IP3 and culminate in an increase in cytosolic Ca2+. Mechanisms that remove Ca2+ also exert an important influence on the net Ca2+ level. The SERCA pump resequesters Ca2+ into the ER and the PMCA transports Ca2+ to the extracellular side. Two key features of the PMCA are its stimulation by Ca2+-calmodulin and by PKA-dependent phosphorylation (Bers, 2001) but in most of the mathematical models this pump is represented with a simple Michaelis-Menten formulation due to its small contribution to the overall Ca2+ fluxes. This is not the case in T cells, Bautista et al (2002) showed that this pump is the primary means of Ca2+ extrusion in T cells and its activity is modulated by Ca2+ enabling the cell to adapt to higher Ca2+ values during T cell activation. Additionally once [Ca2+]i returned to baseline levels the PMCA recovered slowly with a time constant of ∼ 4 min providing a “memory” of previous [Ca2+]i. We created a first order kinetics model of the PMCA that mimics its activation and recovery as function of [Ca2+]i (Vmax increased from 30 to 60 nM s−1, Km decreased from 500 to 400 nM when fully activated) and incorporated into a mathematical description of Ca2+ signaling in T cells (LymphoLAB). Our results indicate that modulation of the PMCA activity improves the stability of Ca2+ signaling by adjusting the pump rate to Ca2+ influx even at high [Ca2+]i levels (preventing a harmful Ca2+ overload). Moreover the delay in modulation permits small Ca2+ fluxes to increase transiently enhancing Ca2+ signaling dynamics.