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J. Biol. Chem., Vol. 282, Issue 13, 10057-10067, March 30, 2007

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The Spatial Distribution of Inositol 1,4,5-Trisphosphate Receptor Isoforms Shapes Ca²⁺ Waves^*

Erick Hernandez, M. Fatima Leite, Mateus T. Guerra, Emma A. Kruglov^¶, Oscar Bruna-Romero, Michele A. Rodrigues^¶, Dawidson A. Gomes^¶, Frank J. Giordano^¶, Jonathan A. Dranoff^¶, and Michael H. Nathanson^¶1

From the Departments of Pediatrics and ^¶Medicine, Yale University, New Haven, Connecticut 06520 and the Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil

Cytosolic Ca²⁺ is a versatile second messenger that can regulate multiple cellular processes simultaneously. This is accomplished in part through Ca²⁺ waves and other spatial patterns of Ca²⁺ signals. To investigate the mechanism responsible for the formation of Ca²⁺ waves, we examined the role of inositol 1,4,5-trisphosphate receptor (InsP3R) isoforms in Ca²⁺ wave formation. Ca²⁺ signals were examined in hepatocytes, which express the type I and II InsP3R in a polarized fashion, and in AR4-2J cells, a nonpolarized cell line that expresses type I and II InsP3R in a ratio similar to what is found in hepatocytes but homogeneously throughout the cell. Expression of type I or II InsP3R was selectively suppressed by isoform-specific DNA antisense in an adenoviral delivery system, which was delivered to AR4-2J cells in culture and to hepatocytes in vivo. Loss of either isoform inhibited Ca²⁺ signals to a similar extent in AR4-2J cells. In contrast, loss of the basolateral type I InsP3R decreased the sensitivity of hepatocytes to vasopressin but had little effect on the initiation or spread of Ca²⁺ waves across hepatocytes. Loss of the apical type II isoform caused an even greater decrease in the sensitivity of hepatocytes to vasopressin and resulted in Ca²⁺ waves that were much slower and delayed in onset. These findings provide evidence that the apical concentration of type II InsP3Rs is essential for the formation of Ca²⁺ waves in hepatocytes. The subcellular distribution of InsP3R isoforms may critically determine the repertoire of spatial patterns of Ca²⁺ signals.

Received for publication, January 25, 2007

^* This work was supported by a postdoctoral research fellowship award from the American Liver Foundation, a grant-in-aid from the American Heart Association, and National Institutes of Health Grants DK45710, DK57751, DK34989, DK61747, DK07356, and TW01451. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Digestive Diseases, Rm. TAC S241D, Yale University School of Medicine, 1 Gilbert St., New Haven, CT 06520-8019. Tel.: 203-785-7312; Fax: 203-785-4306; E-mail: michael.nathanson{at}yale.edu.

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