title: Effects of insulin-like growth factor-1 (IGF-1) receptor signaling on rates of apoptosis in retina of dopamine beta hydroxylase (Dbh-/-) knockout mice.
abstract: We have investigated whether insulin-like growth factor-1 (IGF-1) receptor signaling alters rates of apoptosis in dopamine beta-hydroxylase (Dbh(-/-)) knockout mice. Retinal lysates from Dbh(-/-) and their heterozygote littermates (Dbh(+/-)) were used to examine the role of norepinephrine in the regulation of IGF-1 receptor signaling and apoptosis in the retina. Western blot analysis was done for protein levels of total and phosphorylated IGF-1 receptor, insulin receptor substrate-1 (IRS-1), insulin receptor substrate-2 (IRS-2), and Akt. A caspase 3 ELISA and dopamine ELISA were done on retinal lysates. To verify which regions of the retina were undergoing apoptosis, TUNEL labeling was performed. No changes in dopamine were noted between the KO and heterozygote mice. IGF-1 receptor phosphorylation was significantly decreased in Dbh(-/-) mice as compared to their heterozygote littermates (P<0.05 vs. heterozygous mice). IRS-1 protein phosphorylation was significantly decreased in KO mice (P<0.05 vs. heterozygous mice), while no significant changes were noted in IRS-2 protein phosphorylation. Akt protein phosphorylation was also reduced in the KO mice, likely leading to increased cleaved caspase 3 levels. The increase in apoptosis in the Dbh(-/-) mice occurred predominantly in the inner retina. Our results suggest that IGF-1 receptor signaling is reduced in the retina of mice with dysfunctional adrenergic receptor signaling. The data also indicate that IGF-1 receptor signaling occurs primarily through IRS-1, rather than IRS-2. The reduction in Akt phosphorylation, likely through reduced IGF-1 receptor signaling, could explain the increase in cleaved caspase 3, leading to apoptosis. These results suggest that alterations in adrenergic receptor signaling modulate IGF-1 receptor signaling, which can regulate apoptosis in the retina.
authors.affiliation: Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Surekha Rani
authors.initials: SR
authors.lastname: Panjala
authors.forename: Steven A
authors.initials: SA
authors.lastname: Thomas
authors.forename: Jena J
authors.initials: JJ
authors.lastname: Steinle
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004299:Dopamine beta-Hydroxylase / Q000172:deficiency / Q000235:genetics*; D020287:In Situ Nick-End Labeling; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009638:Norepinephrine / Q000378:metabolism*; D009928:Organ Specificity; D010766:Phosphorylation; D020033:Protein Isoforms; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D012160:Retina / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D020033:Protein Isoforms; D004299:Dopamine beta-Hydroxylase; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D004298:Dopamine; D009638:Norepinephrine