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1 Pharmacology & Physiology, UMDNJ - NJ Medical School, Newark, NJ, USA
* To whom correspondence should be addressed. E-mail: reeves{at}umdnj.edu.
The bovine cardiac sodium-calcium exchanger (NCX1.1) was expressed in Chinese hamster ovary cells. The surface distribution of the exchanger protein, externally tagged with the hemagglutinin (HA) epitope, was associated with underlying actin filaments in regions of cell-to-cell contact and also along stress fibers. After treating cells with cytochalasin D, NCX1.1 protein co-localized with patches of fragmented F-actin. In contrast, an HA-tagged deletion mutant of NCX1.1 that is missing much of the exchanger's central hydrophilic domain, 
(241-680), did not associate with F-actin. In cells expressing the wild-type exchanger, cytochalasin D inhibited allosteric Ca2+ activation of NCX activity, as shown by a prolongation of the lag phase of low Ca2+ uptake following the initiation of the reverse (Ca2+ influx) mode of NCX activity. Other agents that perturbed F-actin structure (methyl-
-cyclodextrin , latrunculin B, and jasplakinolide) also increased the duration of lag phase. In contrast, when reverse-mode activity was initiated following allosteric Ca2+ activation, both cytochalasin D and methyl--cyclodextrin stimulated NCX activity by ~70%. The activity of the (241-680) mutant, which does not require allosteric Ca2+ activation, was also stimulated by cytochalasin D and methyl--cyclodextrin. The increased activity following these treatments appeared to reflect an increased amount of exchanger protein at the cell surface. We conclude that the wild-type NCX1.1 associates with the F-actin cytoskeleton, probably through interactions involving the exchanger's central hydrophilic domain, and that this association interferes with allosteric Ca2+ activation.
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