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Spatial Distribution of Ca²⁺ Signals during Repetitive Depolarizing Stimuli in Adrenal Chromaffin Cells

Department of Physiology, UCLA School of Medicine, Los Angeles, California 90095

Correspondence: Address reprint requests to Jonathan R. Monck, Dept. of Physiology, Center for Health Sciences, 53-263, UCLA School of Medicine, 10833 Le Conte Ave., Los Angeles, CA 90095. Tel.: 310-825-0932; Fax: 310-206-3788; E-mail: jrmonck{at}mednet.ucla.edu.

Exocytosis in adrenal chromaffin cells is strongly influenced by the pattern of stimulation. To understand the dynamic and spatial properties of the underlying Ca²⁺ signal, we used pulsed laser Ca²⁺ imaging to capture Ca²⁺ gradients during stimulation by single and repetitive depolarizing stimuli. Short single pulses (10–100 ms) lead to the development of submembrane Ca²⁺ gradients, as previously described (F. D. Marengo and J. R. Monck, 2000, Biophysical Journal, 79:1800–1820). Repetitive stimulation with trains of multiple pulses (50 ms each, 2Hz) produce a pattern of intracellular Ca²⁺ increase that progressively changes from the typical Ca²⁺ gradient seen after a single pulse to a Ca²⁺ increase throughout the cell that peaks at values 3–4 times higher than the maximum values obtained at the end of single pulses. After seven or more pulses, the fluorescence increase was typically larger in the interior of the cell than in the submembrane region. The pattern of Ca²⁺ gradient was not modified by inhibitors of Ca²⁺-induced Ca²⁺ release (ryanodine), inhibitors of IP₃-induced Ca²⁺ release (xestospongin), or treatments designed to deplete intracellular Ca²⁺ stores (thapsigargin). However, we found that the large fluorescence increase in the cell interior spatially colocalized with the nucleus. These results can be simulated using mathematical models of Ca²⁺ redistribution in which the nucleus takes up Ca²⁺ by active or passive transport mechanisms. These results show that chromaffin cells can respond to depolarizing stimuli with different dynamic Ca²⁺ signals in the submembrane space, the cytosol, and the nucleus.