Insulin augments gonadotropin-releasing hormone induction of translation in LbetaT2 cells.
The integrated signaling of insulin and gonadotropin-releasing hormone in the pituitary gonadotropes may have a profound bearing on reproductive function, although the cross-receptor signaling mechanisms are unclear. We demonstrate that the insulin receptor is constitutively localized to non-caveolar lipid raft microdomains in the pituitary gonadotrope cell line LbetaT2. The localization to rafts is consistent with similar localization of the GnRH receptor. Insulin receptor phosphorylation occurs in raft domains and activates the downstream signaling targets Insulin Receptor Substrate1 and Akt/Protein Kinase B. Although insulin alone does not strongly activate the extracellular signal-regulated kinase second messenger cascade, co-stimulation potentiates the phosphorylation of the extracellular signal-regulated kinase by gonadotropin-releasing hormone. The co-stimulatory effect of insulin and gonadotropin-releasing hormone is also evident in increased activation of cap-dependent translation. In contrast, co-stimulation attenuates Akt/Protein Kinase B activation. Our results show that both gonadotropin-releasing hormone and insulin are capable of mutually altering their respective regulatory signaling cascades. We suggest that this provides a mechanism to integrate neuropeptide and energy homeostatic signals to modulate reproductive function.
Navratil
Amy M
AM
Department of Reproductive Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0674, USA.
Song
Hyunjin
H
Hernandez
Jeniffer B
JB
Cherrington
Brian D
BD
Santos
Sharon J
SJ
Low
Janine M
JM
Do
Minh-Ha T
MH
Lawson
Mark A
MA
D000818:Animals; D021941:Caveolae / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D052681:Gonadotrophs / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology*; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects*; D020033:Protein Isoforms / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012315:RNA Caps / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism
D007328:Insulin; D020033:Protein Isoforms; D012315:RNA Caps; D007987:Gonadotropin-Releasing Hormone; D002784:Cholesterol; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases