title: Insulin-like growth factor-1 induces an inositol 1,4,5-trisphosphate-dependent increase in nuclear and cytosolic calcium in cultured rat cardiac myocytes.
abstract: 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 Ca(2+)(i) levels apparent both in the nucleus and cytosol, releasing this ion from intracellular stores through an inositol 1,4,5-trisphosphate (IP(3))-dependent signaling pathway. Intracellular IP(3) levels increased after IGF-1 stimulation in both the presence and absence of extracellular Ca(2+). A different spatial distribution of IP(3) 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 Ca(2+)-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 Ca(2+) released by stimulation with IGF-1 was initially contained in the perinuclear region. The IGF-1-induced increase on Ca(2+)(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 betaARKct (a peptide inhibitor of Gbetagamma signaling). Pertussis toxin also prevented the IGF-1-dependent IP(3) mass increase. Genistein treatment largely decreased the IGF-1-induced changes in both Ca(2+)(i) and IP(3). LY29402 (but not PD98059) also prevented the IGF-1-dependent Ca(2+)(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 Ca(2+)(i) levels in cultured cardiac myocytes through a Gbetagamma subunit of a pertussis toxin-sensitive G protein-PI3K-phospholipase C signaling pathway that involves participation of IP(3).
authors.affiliation: Departament de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago.
authors.forename: Cristian
authors.initials: C
authors.lastname: Ibarra
authors.forename: Manuel
authors.initials: M
authors.lastname: Estrada
authors.forename: Loreto
authors.initials: L
authors.lastname: Carrasco
authors.forename: Mario
authors.initials: M
authors.lastname: Chiong
authors.forename: José L
authors.initials: JL
authors.lastname: Liberona
authors.forename: César
authors.initials: C
authors.lastname: Cardenas
authors.forename: Guillermo
authors.initials: G
authors.lastname: Díaz-Araya
authors.forename: Enrique
authors.initials: E
authors.lastname: Jaimovich
authors.forename: Sergio
authors.initials: S
authors.lastname: Lavandero
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000032:analysis / Q000502:physiology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism*; D005456:Fluorescent Dyes; D019204:GTP-Binding Proteins / Q000502:physiology; D006321:Heart / Q000187:drug effects; D007150:Immunohistochemistry; D015544:Inositol 1,4,5-Trisphosphate / Q000502:physiology*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure*; D009543:Nifedipine / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis / Q000502:physiology; D012433:Ryanodine / Q000494:pharmacology; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D005456:Fluorescent Dyes; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D012433:Ryanodine; D007334:Insulin-Like Growth Factor I; D015544:Inositol 1,4,5-Trisphosphate; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D009543:Nifedipine; D002118:Calcium