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RECEPTORS AND SIGNAL TRANSDUCTION

Immunolocalization of type 2 inositol 1,4,5-trisphosphate receptors in cardiac myocytes from newborn mice

¹Research Services, Edward Hines Jr. Department of Veterans Affairs Hospital, Hines 60141; and ²Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois 60612

Submitted 6 January 2004 ; accepted in final form 14 June 2004

The precise localization and role of inositol 1,4,5-trisphosphate (InsP₃) receptors (InsP₃Rs) in cardiac muscle cells are largely unknown. It is believed that waves and oscillations in cytosolic free calcium triggered by activation of InsP₃Rs underlie modifications of cellular responses that lead to changes in gene expression in other cells. However, how changes in cytosolic calcium alter gene expression in cardiac cells is unknown. Moreover, it is unclear how changes in cytosolic calcium that alter gene expression do so independently of effects of calcium on other cellular functions, such as contraction. Here we show that InsP₃R type 2 is the only isoform present in cardiac myocytes isolated from neonatal mouse ventricles. We also show that type 2 InsP₃Rs are associated with the nucleus and that activation of type 2 InsP₃Rs with endothelin-1 or phenylephrine selectively increases transcription of atrial natriuretic factor and skeletal -actin. Type 2 InsP₃Rs are also in striations. Activation of InsP₃Rs with adenophostin A in permeabilized cells induced calcium release in the nuclear domain and other regions of the cell away from the nucleus. Agonist-induced increase in gene expression and calcium release were blocked by the InsP₃R inhibitors 2-aminoethoxydiphenyl borate and xestospongin C. The spatial separation of type 2 InsP₃Rs provides support for the concept that microdomains of calcium discretely alter various cell processes. Our experiments suggest that calcium released by InsP₃Rs in the nuclear domain provides a direct mechanism for the control of gene expression, whereas release of calcium in the cytoplasm may modulate other processes, such as contraction.

calcium release channels; cell signaling; calcium handling; inositol trisphosphate receptors

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