Control of calcium oscillations by membrane fluxes

Abstract

It is known that Ca 2؉ influx plays an important role in the modulation of inositol trisphosphate-generated Ca 2؉ oscillations, but controversy over the mechanisms underlying these effects exists. In addition, the effects of blocking membrane transport or reducing Ca 2؉ entry vary from one cell type to another; in some cell types oscillations persist in the absence of Ca 2؉ entry (although their frequency is affected), whereas in other cell types oscillations depend on Ca 2؉ entry. We present theoretical and experimental evidence that membrane transport can control oscillations by controlling the total amount of Ca 2؉ in the cell (the Ca 2؉ load). Our model predicts that the cell can be balanced at a point where small changes in the Ca 2؉ load can move the cell into or out of oscillatory regions, resulting in the appearance or disappearance of oscillations. Our theoretical predictions are verified by experimental results from HEK293 cells. We predict that the role of Ca 2؉ influx during an oscillation is to replenish the Ca 2؉ load of the cell. Despite this prediction, even during the peak of an oscillation the cell or the endoplasmic reticulum may not be measurably depleted of Ca 2؉ .I n response to an increased concentration of inositol trisphosphate (IP 3 ), oscillations in the concentration of free intracellular calcium (Ca 2ϩ ) occur in many cell types and are important for the control of many cellular functions (1-4). In nonexcitable cells, such as epithelial cells, these oscillations occur as the result of Ca 2ϩ flux into and out of the endoplasmic reticulum (ER). However, although the oscillations result from the cycling of Ca 2ϩ between the ER and the cytoplasm, the transport of Ca 2ϩ across the cell membrane can have a dramatic effect on these oscillations.Although Ca 2ϩ influx is known to be important, disagreement exists, first, over the mechanisms by which Ca 2ϩ influx is modulated during a Ca 2ϩ oscillation, and, second, over the role played by Ca 2ϩ influx. The capacitative entry hypothesis proposes that depletion of ER Ca 2ϩ causes enhanced entry of Ca 2ϩ across the plasma membrane (5-9). Often, although not necessarily, in this scenario, Ca 2ϩ entry is necessary for the refilling of the ER, and thus oscillation frequency is controlled by the refilling time (10, 11). Although capacitative entry is certainly an important factor during the response to a maximal stimulus, other investigators have pointed to a lack of direct evidence that it plays an important role during smaller stimuli that generate oscillatory behavior (12). They maintain that Ca 2ϩ influx, under these conditions, is controlled by a noncapacitative pathway involving arachidonic acid and that the purpose of the influx is to increase the likelihood that low levels of IP 3 will induce Ca 2ϩ release from internal stores (13). This controversy is complicated by the fact that, in some cell types, Ca 2ϩ oscillations persist in the absence of Ca 2ϩ influx (14-16), whereas in other cell types, oscillations depend absolutely on influx (17, ...

Dynamics of a minimal neural model consisting of an astrocyte, a neuron, and an interneuron

“…These data also show that, apart from a small interval of k 5 values, the increase of the rate of extrusion of the intracellular calcium from the astrocyte determines a progressive reduction of the oscillation amplitude. This last fact is in agreement with the experimental results reported in Parri and Crunelli [56] and also with those of Lavrentovich and Hemkin [55] and Sneyd et al [54]. On the contrary, there is an increase of the period of calcium oscillation as the parameter k 5 increases.…”

“…Such a constraint implies that in this condition the quantity of calcium entering the cell is completely balanced by that extruded from the astrocyte. The importance of the membrane transport of Ca 2+ in the control of calcium oscillations was shown recently by Sneyd et al [54]. Similar results were obtained also by Lavrentovich and Hemkin [55].…”

“…An important difference of the model used in this paper with that employed by Lavrentovich and Hemkin [55] and Sneyd et al [54] concerns the modulation effects arising from the presence of the extracellular ATP. Thus, a relevant problem-worthy to be investigated-is to understand how the above results change when extracellular ATP is present.…”

Membrane associated complexes : new approach to calcium dynamics modelling

“…This assumption can be justified because usually the calcium transport across the cell membrane is much slower than the calcium transport between the internal compartments [35]. Additionally, according to [35], calcium oscillations can still occur, provided that the total amount of Ca 2+ in the cell is in a proper range, even if calcium transport across the plasma membrane is blocked.…”

“…Additionally, according to [35], calcium oscillations can still occur, provided that the total amount of Ca 2+ in the cell is in a proper range, even if calcium transport across the plasma membrane is blocked. Adding equations (3.4) and (3.5) we obtain d dt (CaPr + Pr) = 0, which implies that the total concentration Pr tot of calcium binding sites (i.e.…”