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J. Biol. Chem., Vol. 279, Issue 9, 7554-7565, February 27, 2004

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Insulin-like Growth Factor-1 Induces an Inositol 1,4,5-Trisphosphate-dependent Increase in Nuclear and Cytosolic Calcium in Cultured Rat Cardiac Myocytes^*

Cristian Ibarra¶, Manuel Estrada||, Loreto Carrasco¶, Mario Chiong, José L. Liberona||, César Cardenas||, Guillermo Díaz-Araya**, Enrique Jaimovich||, and Sergio Lavandero||

From the Departamentos de Bioquímica y Biología Molecular y ^**Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, the ^||Instituto de Ciencias Biomédicas, Facultad de Medicina, the Centro FONDAP Estudios Moleculares de la Célula, Universidad de Chile, Santiago 6640750, Chile

In the heart, insulin-like growth factor-1 (IGF-1) is a pro-hypertrophic and anti-apoptotic peptide. In cultured rat cardiomyocytes, IGF-1 induced a fast and transient increase in Ca²⁺_i levels apparent both in the nucleus and cytosol, releasing this ion from intracellular stores through an inositol 1,4,5-trisphosphate (IP₃)-dependent signaling pathway. Intracellular IP₃ levels increased after IGF-1 stimulation in both the presence and absence of extracellular Ca²⁺. A different spatial distribution of IP₃ receptor isoforms in cardiomyocytes was found. Ryanodine did not prevent the IGF-1-induced increase of Ca²⁺_i levels but inhibited the basal and spontaneous Ca²⁺_i oscillations observed when cardiac myocytes were incubated in Ca²⁺-containing resting media. Spatial analysis of fluorescence images of IGF-1-stimulated cardiomyocytes incubated in Ca²⁺-containing resting media showed an early increase in Ca²⁺_i, initially localized in the nucleus. Calcium imaging suggested that part of the Ca²⁺ released by stimulation with IGF-1 was initially contained in the perinuclear region. The IGF-1-induced increase on Ca²⁺_i levels was prevented by 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-AM, thapsigargin, xestospongin C, 2-aminoethoxy diphenyl borate, U-73122, pertussis toxin, and ARKct (a peptide inhibitor of G signaling). Pertussis toxin also prevented the IGF-1-dependent IP₃ mass increase. Genistein treatment largely decreased the IGF-1-induced changes in both Ca²⁺_i and IP₃. LY29402 (but not PD98059) also prevented the IGF-1-dependent Ca²⁺_i increase. Both pertussis toxin and U73122 prevented the IGF-1-dependent induction of both ERKs and protein kinase B. We conclude that IGF-1 increases Ca²⁺_i levels in cultured cardiac myocytes through a G subunit of a pertussis toxin-sensitive G protein-PI3K-phospholipase C signaling pathway that involves participation of IP₃.

Received for publication, October 22, 2003 , and in revised form, December 1, 2003.

^* This work was supported in part by Fondo Nacional de Ciencia y Tecnología (FONDECYT) Grants 1010246 (to S. L.), FONDAP 15010006 (to S. L. and E. J.) Beca Apoyo Tesis-2002 and Graduate Grant UCH PG 75/2001 (to L. C.). 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.

^¶ Supported by fellowships from the Consejo Nacional de Investigaciones Científicas y Técnicas, Chile.

To whom correspondence may be addressed: Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Independencia 1027, Santiago 6640750, Chile. Tel.: 562-678-6510; E-mail: ejaimovi{at}machi.med.uchile.cl. To whom correspondence may be addressed: Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Olivos 1007, Santiago 6640750, Chile. Tel.: 562-678-2919; Fax: 562-737-8920; E-mail: slavander{at}uchile.cl.

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