Genetically reducing alpha 2 Na+ pumps by approximately 50% in mice augmented evoked Ca2+ transients despite normal cytosolic Na+ and resting Ca2+ concentrations.
Alpha 2/alpha 3 Na(+) pumps control local cytosolic Na(+) in PLasmERosomes, which in turn modulates local Ca(2+), endoplasmic reticulum Ca(2+) storage, and Ca(2+) signaling via the Na/Ca exchanger in neurons and astrocytes.
Immunocytochemistry reveals that the Na/Ca exchanger (NCX) in neuronal somata and astrocytes is confined to plasma membrane (PM) microdomains that overlie sub-PM (junctional) endoplasmic reticulum (jER). By contrast, the PM Ca(2+) pump (PMCA) is more uniformly distributed in the PM. At presynaptic nerve terminals, the NCX distribution is consistent with that observed in the neuronal somata, but the PMCA is clustered at the active zones. Thus, the PMCA, with high affinity for Ca(2+) (K(d) congruent with 100 nM), may keep active zone Ca(2+) very low and thereby "reprime" the vesicular release mechanism following activity. NCX, with lower affinity for Ca(2+) (K(d) congruent with 1,000 nM), on the other hand, may extrude Ca(2+) that has diffused away from the active zones and been temporarily sequestered in the endoplasmic reticulum. The PL microdomains that contain the NCX also contain Na(+) pump high ouabain affinity alpha2 (astrocytes) or alpha 3 (neurons) subunit isoforms (IC(50) congruent with 5-50 nM ouabain). In contrast, the alpha1 isoform (low ouabain affinity in rodents; IC(50) >10,000 nM), like the PMCA, is more uniformly distributed in these cells. The sub-PM endoplasmic reticulum in neurons (and probably glia and other cell types as well) and the adjacent PM form junctions that resemble cardiac muscle dyads. We suggest that the PM microdomains containing NCX and alpha 2/alpha 3 Na(+) pumps, the underlying jER, and the intervening tiny volume of cytosol (<10(-18) l) form functional units (PLasmERosomes); diffusion of Na(+) and Ca(2+) between these cytosolic compartments and "bulk" cytosol may be markedly restricted. The activity of the Na(+) pumps with alpha 2/alpha 3 subunits may thus regulate NCX activity and jER Ca(2+) content. This view is supported by studies in mice with genetically reduced (by congruent with 50%) alpha 2 Na(+) pumps: evoked Ca(2+) transients were augmented in these cells despite normal cytosolic Na(+) and resting Ca(2+) concentrations (Na(+)(CYT) and Ca(2+)(CYT)). We conclude that alpha 2/alpha 3 Na(+) pumps control PLasmERosome (local) Na(+)(CYT). This, in turn, via NCX, modulates local Ca(2+)(CYT), jER Ca(2+) storage, Ca(2+) signaling, and cell responses.
Blaustein et al. (Fri,) reported a other. Genetically reduced alpha 2 Na(+) pumps vs. Normal alpha 2 Na(+) pumps was evaluated on Evoked Ca(2+) transients. Genetically reducing alpha 2 Na+ pumps by approximately 50% in mice augmented evoked Ca2+ transients despite normal cytosolic Na+ and resting Ca2+ concentrations.