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Vol. 273, Issue 3, 1519-1528, January 16, 1998

Intercellular Calcium Signaling via Gap Junction in Connexin-43-transfected Cells

From the Department of Medicine and Pathophysiology, Osaka University Medical School, Suita, Osaka 565, Japan

In excitable cells, intracellular Ca²⁺ is released via the ryanodine receptor from the intracellular Ca²⁺ storing structure, the sarcoplasmic reticulum. To determine whether this released Ca²⁺ propagates through gap junctions to neighboring cells and thereby constitutes a long range signaling network, we developed a cell system in which cells expressing both connexin-43 and ryanodine receptor are surrounded by cells expressing only connexin-43. When the ryanodine receptor in cells was activated by caffeine, propagation of Ca²⁺ from these caffeine-responsive cells to neighboring cells was observed with a Ca²⁺ imaging system using fura-2/AM. Inhibitors of gap junctional communication rapidly and reversibly abolished this propagation of Ca²⁺. Together with the electrophysiological analysis of transfected cells, the observed intercellular Ca²⁺ wave was revealed to be due to the reconstituted gap junction of transfected cells.

We next evaluated the functional roles of cysteine residues in the extracellular loops of connexin-43 in gap junctional communication. Mutations of Cys⁵⁴, Cys¹⁸⁷, Cys¹⁹², and Cys¹⁹⁸ to Ser showed the failure of Ca²⁺ propagation to neighboring cells in accordance with the electrical uncoupling between transfected cells, whereas mutations of Cys⁶¹ and Cys⁶⁸ to Ser showed the same pattern as the wild type. [¹⁴C]Iodoacetamide labeling of free thiols of cysteine residues in mutant connexin-43s showed that two pairs of intramolecular disulfide bonds are formed between Cys⁵⁴ and Cys¹⁹² and between Cys¹⁸⁷ and Cys¹⁹⁸. These results suggest that intercellular Ca²⁺ signaling takes place in cultured cells expressing connexin-43, leading to their own synchronization and that the extracellular disulfide bonds of connexin-43 are crucial for this process.

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