A minimal mathematical model to study cytoplasmic Ca2+ kinetics in cells

VIGIL MAXIMILIANO ANGEL; SAFFIOTI NICOLÁS; RINALDI, DEBORA; MANGIALAVORI IRENE; ROLANDO C ROSSI; ROSSI J. P. F. C.; FERREIRA GOMES, MARIELA

BUENOS AIRES

Jornada; Biofísica en tiempos de COVID-19 : Primeras Jornadas Virtuales SAB 2020; 2020

Sociedad Argentina de Biofísica

Calcium (Ca2+) is a critical cofactor and signaling mediator in cells, and theconcentration of cytosolic Ca2+ ([Ca2+]cyt) is highly regulated. All cells must maintain alow concentration of [Ca2+]cyt (~100 nM) to maintain viability while using their increaseas a versatile signaling pathway. It is mainly controlled through a combination of twoclosely linked processes: Ca2+ release from the endoplasmic reticulum (ER) and Ca 2+entry across the plasma membrane (PM). Resting cells maintain cytosolic [Ca2+] in thenM range through sarcoplasmic reticulum Ca2+ ATPase (SERCA) and plasma membraneCa2+ ATPase (PMCA) pumps. Our group has studied the role of PMCA in the removal ofcalcium under different experimental conditions using fluorescence time-coursemeasurements [1,2,3]. The objective of this work is to obtain a simple model to study therole of PMCA in the removal of calcium from the cells. In a typical experiment, [Ca2+]cytkinetics shows a transient increase upon the applied stimulus, followed by a slowdecrease until a stationary level is reached. To analyze our results, we constructed aminimal mathematical model to describe [Ca2+]cyt kinetics in HEK293T cells. Our modelcan describe both the reticulum Ca2+ depletion and the Ca2+ influx after Store OperatedChannels (SOCs) activation. It showed that the rate of PMCA activation is critical, and itmust be slower than the rate of calmodulin activation. On the other hand, it wasnecessary to considerer the effect of calcium buffering in cells to fit the model to theexperimental data. In conclusion, we constructed a simple model which will allow us toanalyze how PMCA responses in a living cell.References1 Dalghi MG, Rossi JP. Cortical cytoskeleton dynamics regulates plasma membranecalcium ATPase isoform-2 (PMCA2) activity. Biochim Biophys Acta Mol Cell Res. 2017;1864(8):1413-14242 Ferreira-Gomes MS, Rossi JP. Selectivity of plasma membrane calcium ATPase(PMCA)‑mediated extrusion of toxic divalent cations in vitro and in cultured cells. ArchToxicol (2018) 92:273?2883 Ontiveros M, Ferreira-Gomes MS. Natural flavonoids inhibit the plasma membraneCa2+-ATPase. Biochemical Pharmacology 1864 (2017) 1413-1424AcknowldegmentsThis work was supported by ANPCYT, CONICET, UBA