The plasma membrane Ca²+ ATPase and the plasma membrane sodium calcium exchanger cooperate in the regulation of cell calcium

Abstract

Calcium is an ambivalent signal: it is essential for the correct functioning of cell life, but may also become dangerous to it. The plasma membrane Ca(2+) ATPase (PMCA) and the plasma membrane Na(+)/Ca(2+) exchanger (NCX) are the two mechanisms responsible for Ca(2+) extrusion. The NCX has low Ca(2+) affinity but high capacity for Ca(2+) transport, whereas the PMCA has a high Ca(2+) affinity but low transport capacity for it. Thus, traditionally, the PMCA pump has been attributed a housekeeping role in maintaining cytosolic Ca(2+), and the NCX the dynamic role of counteracting large cytosolic Ca(2+) variations (especially in excitable cells). This view of the roles of the two Ca(2+) extrusion systems has been recently revised, as the specific functional properties of the numerous PMCA isoforms and splicing variants suggests that they may have evolved to cover both the basal Ca(2+) regulation (in the 100 nM range) and the Ca(2+) transients generated by cell stimulation (in the μM range).

Figure 1.

A schematic representation of the structures involved in cellular Ca²⁺ homeostasis. The model shows a cell with its Ca²⁺-transporting systems: Ca²⁺-ATPases (plasma membrane and sarco/endoplasmic reticulum, PMCA and SERCA), plasma membrane (PM) Ca²⁺ channels, Na⁺/Ca²⁺ exchangers (NCX and NCLX), 1,4,5-triphosphate receptor (IP₃R) and ryanodine receptor (RyR), the electrophoretic mitochondrial uptake uniporter (U). Mitochondria are drawn as yellow ellipses, nucleus as orange circle and endoplasmic reticulum is colored in red. The different Ca²⁺-transporting systems cooperate to maintain the Ca²⁺ concentration gradient between the extracellular and the intracellular ambient.

Figure 2.

(A) Topology model of PMCA. The pump is organized in the membrane with ten transmembrane domains connected on the external side by short loops. The cytosolic portion of the pump contains the catalytic center and other functionally important domains. The ATP binding site is indicated with a yellow circle. Acidic phospholipid binding domain (PL) and Calmodulin binding domain (CaMBD) are represented with pale blue boxes. (B) Deduced 3D structure of the PMCA pump. The three-dimensional structure of the PMCA pump has been obtained modeling it on that of the SERCA pump (Toyoshima et al. 2000). The image is a kind gift of Dr. M. Hilge (Nijmegen, Holland).

Figure 3.

(A) Topology model of NCX. The nine transmembrane domains comprise the two putative transport repeat regions: α-1 and α-2. XIP region, CBD1 and CBD2 are indicated by yellow boxes. The red spheres indicate the Ca²⁺ binding sites position (B) Hypothetical structural model of the intact NCX. The nine transmembrane domains are shown as yellow α-helices, the CLD as blue α-helices and the CBD1 and CBD2 β repeats as red and green β strands, respectively. The red spheres indicate the Ca²⁺ binding sites position. The image is a kind gift of Dr. M. Hilge (Nijmegen, Holland).