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J. Cell Biol. 166 (1): 111-119

Copyright © 2004 by the Rockefeller University Press.


Extracellular calcium acts as a "third messenger" to regulate enzyme and alkaline secretion

Rosa Caroppo 1 , Andrea Gerbino 1 , Gregorio Fistetto 1 , Matilde Colella 1 2 , Lucantonio Debellis 1 , Aldebaran M. Hofer 2 , , and Silvana Curci 1 2

1 Dipartimento di Fisiologia Generale ed Ambientale, Università di Bari, 70126 Bari, Italy
2 Department of Surgery, Harvard Medical School, Brigham and Women's Hospital and the Boston VA Healthcare System, West Roxbury, MA 02132

Address correspondence to S. Curci, Dept. of Surgery, Harvard Medical School, Brigham and Women's Hospital and the Boston VA Healthcare System, 1400 VFW Parkway, West Roxbury, MA 02132. Tel.: (617) 323-7700, ext. 5902. Fax: (617) 363-5592. email: scurci{at}

Abstract: It is generally assumed that the functional consequences of stimulation with Ca2+-mobilizing agonists are derived exclusively from the second messenger action of intracellular Ca2+, acting on targets inside the cells. However, during Ca2+ signaling events, Ca2+ moves in and out of the cell, causing changes not only in intracellular Ca2+, but also in local extracellular Ca2+. The fact that numerous cell types possess an extracellular Ca2+ "sensor" raises the question of whether these dynamic changes in external [Ca2+] may serve some sort of messenger function. We found that in intact gastric mucosa, the changes in extracellular [Ca2+] secondary to carbachol-induced increases in intracellular [Ca2+] were sufficient and necessary to elicit alkaline secretion and pepsinogen secretion, independent of intracellular [Ca2+] changes. These findings suggest that extracellular Ca2+ can act as a "third messenger" via Ca2+ sensor(s) to regulate specific subsets of tissue function previously assumed to be under the direct control of intracellular Ca2+.

Key Words: extracellular Ca2+-sensing receptor; polarized epithelial cells; pH microelectrodes; interstitial space; adenylyl cyclase

Abbreviations used in this paper: AC, adenylyl cyclase; CaR, Ca2+-sensing receptor; DIDS, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid; OC, oxyntopeptic cell; PMCA, plasma membrane Ca2+ ATPase; PTX, pertussis toxin; SQ 22,536, 9-(tetrahydro-2-furanyl)-9H-purin-6-amine; tBHQ, 2,5-di-(tert-butyl)hydroquinone.

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