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J. Biol. Chem., Vol. 277, Issue 18, 16313-16323, May 3, 2002

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Molecular Basis for Pacemaker Cells in Epithelia^*

M. Fatima Leite, Keiji Hirata^§, Thomas Pusl^§, Angela D. Burgstahler^§, Keisuke Okazaki^¶, J. Miguel Ortega, Alfredo M. Goes, Marco A. M. Prado^**, David C. Spray, and Michael H. Nathanson^§§§

From the  Department of Physiology and Biophysics, Universidade Federal de Minas Gerais (UFMG), 31270-901 Belo Horizonte, Brazil, the ^§ Departments of Medicine and Cell Biology, Yale University, New Haven, Connecticut 06520-8019, the ^¶ Department of Surgery, University of Occupational and Environmental Health, Kitakyushu, 8078555, Japan, the  Department of Biochemistry and Immunology, UFMG, Belo Horizonte, Brazil, the ^** Department of Pharmacology, UFMG, Belo Horizonte, Brazil, and the  Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461

Intercellular signaling is highly coordinated in excitable tissues such as heart, but the organization of intercellular signaling in epithelia is less clear. We examined Ca²⁺ signaling in hepatoma cells expressing the hepatocyte gap junction protein connexin32 (cx32) or the cardiac gap junction protein cx43, plus a fluorescently tagged V_1a vasopressin receptor (V_1aR). Release of inositol 1,4,5-trisphosphate (InsP₃) in wild type cells increased Ca²⁺ in the injected cell but not in neighboring cells, while the Ca²⁺ signal spread to neighbors when gap junctions were expressed. Photorelease of caged Ca²⁺ rather than InsP₃ resulted in a small increase in Ca²⁺ that did not spread to neighbors with or without gap junctions. However, photorelease of Ca²⁺ in cells stimulated with low concentrations of vasopressin resulted in a much larger increase in Ca²⁺, which spread to neighbors via gap junctions. Cells expressing tagged V_1aR similarly had increased sensitivity to vasopressin, and could signal to neighbors via gap junctions. Higher concentrations of vasopressin elicited Ca²⁺ signals in all cells. In cx32 or cx43 but not in wild type cells, this signaling was synchronized and began in cells expressing the tagged V_1aR. Thus, intercellular Ca²⁺ signals in epithelia are organized by three factors: 1) InsP₃ must be generated in each cell to support a Ca²⁺ signal in that cell; 2) gap junctions are necessary to synchronize Ca²⁺ signals among cells; and 3) cells with relatively increased expression of hormone receptor will initiate Ca²⁺ signals and thus serve as pacemakers for their neighbors. Together, these factors may allow epithelia to act in an integrated, organ-level fashion rather than as a collection of isolated cells.

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