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

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 Ca ²⁺_i levels but inhibited the basal and spontaneous Ca ²⁺_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 Ca ²⁺-containing resting media showed an early increase in Ca ²⁺_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 βARKct (a peptide inhibitor of Gβγ signaling). Pertussis toxin also prevented the IGF-1-dependent IP₃ mass increase. Genistein treatment largely decreased the IGF-1-induced changes in both Ca ²⁺_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 Gβγ subunit of a pertussis toxin-sensitive G protein-PI3K-phospholipase C signaling pathway that involves participation of IP₃.