Na⁺/H⁺ exchange and Ca²⁺ influx

Cell stimulation raised the cytosolic free Ca2+ concentration, [Ca(2+]i and induces activation of Na+/H+ exchange which raises the cytosolic pH, pHi. Recent studies have addressed the question whether Na+/H+ exchange plays a role in Ca(2+) influx and, specifically, whether a rise in pHi alone suffices to open Ca(2+) channels in the plasma membrane. Artificial cytosolic alkalinization can induce Ca(2+) uptake across the plasma membrane of endothelial cells, lymphocytes and smooth muscle cells. Furthermore, inhibition of Na+/H+ exchange reduces agonist-induced Ca(2+) influx in endothelial cells and platelets which supports the concept that pHi may regulate the opening of Ca(2+) channels in the plasma membrane. Although these findings argue in favour of a role of Na+/H+ exchange in Ca(2+) influx, the onset of pHi and Ca(2+) rises, measured with fluorescent indicators, suggests that the increase in [Ca(2+)]i distinctly precedes the increase in pHi. This challenges the concept that alkalinization per se is a sufficient signal for the opening of Ca(2+) channels in the plasma membrane.