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Allosteric Activation of Sodium–Calcium Exchange Activity by Calcium

Persistence at Low Calcium Concentrations

John P. Reeves and Madalina Condrescu

Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07101

Address correspondence to John P. Reeves, Department of Pharmacology and Physiology, UMDNJ – NJ Medical School, P.O. Box 1709, Newark, NJ 07101-1709. Fax: (973) 972-7950; email: reeves{at}umdnj.edu

The activity of the cardiac Na⁺/Ca²⁺ exchanger is stimulated allosterically by Ca²⁺, but estimates of the half-maximal activating concentration have varied over a wide range. In Chinese hamster ovary cells expressing the cardiac Na⁺/Ca²⁺ exchanger, the time course of exchange-mediated Ca²⁺ influx showed a pronounced lag period followed by an acceleration of Ca²⁺ uptake. Lag periods were absent in cells expressing an exchanger mutant that was not dependent on regulatory Ca²⁺ activation. We assumed that the rate of Ca²⁺ uptake during the acceleration phase reflected the degree of allosteric activation of the exchanger and determined the value of cytosolic Ca²⁺ ([Ca²⁺]_i) at which the rate of Ca²⁺ influx was half-maximal (K_h). After correcting for the effects of mitochondrial Ca²⁺ uptake and fura-2 buffering, K_h values of 300 nM were obtained. After an increase in [Ca²⁺]_i, the activated state of the exchanger persisted following a subsequent reduction in [Ca²⁺]_i to values <100 nM. Thus, within 30 s after termination of a transient increase in [Ca²⁺]_i, exchange-mediated Ca²⁺ entry began without a lag period and displayed a linear rate of Ca²⁺ uptake in most cells; a sigmoidal time course of Ca²⁺ uptake returned 60–90 s after the transient increase in [Ca²⁺]_i was terminated. Relaxation of the activated state was accelerated by the activity of the endoplasmic reticulum Ca²⁺ pump, suggesting that local Ca²⁺ gradients contribute to maintaining exchanger activation after the return of global [Ca²⁺]_i to low values.

Key Words: Chinese hamster ovary cells • fura-2 • digital imaging • mitochondria • SERCA

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