One important mode of Ca2+ influx across the plasma membrane involves Ca2+ release from intracellular Ca2+ store through the inositol 1,4,5-trisphosphate receptors, followed by activation of store-operated Ca2+ (SOC) channels [4].
In pathological conditions, NCX can reversely extrude Na+ for Ca2+ influx and result in intracellular Ca2+ overload, which is referred to as the reverse mode or calcium influx mode of NCX.
We investigated the participation of NCX in ATP-mediated MUC5AC secretion and Ca2+ signaling using KB-R9743, aNCXCX inhibitor that preferentially blocks the reverse Ca2+ influx mode of the transporter (Iwamoto et al., 1996).
SN-6, on the other hand antagonizes with high affinity only the Ca2+-influx mode of NCXs, preferentially of NCX1, while not interfering with Cavs at the concentration used here [29].
ET-1 overproduction and renal ischemia can cause depletion of ATP and development of intracellular acidosis, which can result in accumulation of intracellular Na+ and further activate the reversion of the mode of NCX and subsequently cause Ca2+ influx and ET-1 overproduction, forming a vicious cycle.
Although the reduction of external Na+ is an intervention that increases the driving force for reversed mode NCXpm under a fixed level of intracellular Na+, this manoeuvre was expected to inhibit NCXpm-mediated Ca2+ entry in confluent cells, when Na+ influx triggers the reversed mode of NCXpm.
Simultaneously, the co-transport of Na+ ions can activate the reverse mode of the sodium/calcium exchanger (NCX), leading to an influx of Ca2+ and activating glycogen degradation [ 43].
The operation of NCXpm in Ca2+ entry mode following histamine stimulation is apparently ensured by a pronounced increase in Na+ influx, which would override the forward mode of the exchanger activated by a rise in intracellular Ca2+ concentration.
The Na+-dependent activation of the reverse mode of the Na+/Ca2+ exchanger provides the necessary link to the influx of Ca2+ and the subsequent contraction of myocytes within the physiological range of membrane depolarizations.
