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First published online 15 July 2008
doi: 10.1242/jcs.031997

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Ca²⁺ oscillation frequency regulates agonist-stimulated gene expression in vascular endothelial cells

Liping Zhu^1,2,*, Yougen Luo^1,2,*, Taoxiang Chen^1,3,*, Fengrong Chen^1,2, Tao Wang¹ and Qinghua Hu^1,2,

¹ Key Laboratory of Pulmonary Diseases of Ministry of Health of China
² Department of Pathophysiology, Tongji Medical College, Huazhong Science and Technology University, Wuhan 430030, China
³ Department of Physiology, Wuhan University School of Medicine, Wuhan 430072, China

Author for correspondence (e-mail: qinghuaa{at}mails.tjmu.edu.cn)

Accepted 13 May 2008

A physiological membrane-receptor agonist typically stimulates oscillations, of varying frequencies, in cytosolic Ca²⁺ concentration ([Ca²⁺]_i). Whether and how [Ca²⁺]_i oscillation frequency regulates agonist-stimulated downstream events, such as gene expression, in non-excitable cells remain unknown. By precisely manipulating [Ca²⁺]_i oscillation frequency in histamine-stimulated vascular endothelial cells (ECs), we demonstrate that the gene expression of vascular cell adhesion molecule 1 (VCAM1) critically depends on [Ca²⁺]_i oscillation frequency in the presence, as well as the absence, of histamine stimulation. However, histamine stimulation enhanced the efficiency of [Ca²⁺]_i-oscillation-frequency-regulated VCAM1 gene expression, versus [Ca²⁺]_i oscillations alone in the absence of histamine stimulation. Furthermore, a [Ca²⁺]_i oscillation frequency previously observed to be the mean frequency in histamine-stimulated ECs was found to optimize VCAM1 mRNA expression. All the above effects were abolished or attenuated by blocking histamine-stimulated generation of intracellular reactive oxygen species (ROS), another intracellular signaling pathway, and were restored by supplementary application of a low level of H₂O₂. Endogenous NF-B activity is similarly regulated by [Ca²⁺]_i oscillation frequency, as well as its co-operation with ROS during histamine stimulation. This study shows that [Ca²⁺]_i oscillation frequency cooperates with ROS to efficiently regulate agonist-stimulated gene expression, and provides a novel and general strategy for studying [Ca²⁺]_i signal kinetics in agonist-stimulated downstream events.

Key words: Ca²⁺ oscillation, Reactive oxygen species, Gene expression

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