title: Mixed analog/digital gonadotrope biosynthetic response to gonadotropin-releasing hormone.
abstract: Mammalian reproduction requires gonadotropin-releasing hormone (GnRH)-mediated signaling from brain neurons to pituitary gonadotropes. Because the pulses of released GnRH vary greatly in amplitude, we studied the biosynthetic response of the gonadotrope to varying GnRH concentrations, focusing on extracellular-regulated kinase (ERK) phosphorylation and egr1 mRNA and protein production. The overall average level of ERK activation in populations of cells increased non-cooperatively with increasing GnRH and did not show evidence of either ultrasensitivity or bistability. However, automated image analysis of single-cell responses showed that whereas individual gonadotropes exhibited two response states, inactive and active, both the probability of activation and the average response in activated cells increased with increasing GnRH concentration. These data indicate a hybrid single-cell response having both digital (switch-like) and analog (graded) features. Mathematical modeling suggests that the hybrid response can be explained by indirect thresholding of ERK activation resulting from the distributed structure of the GnRH-modulated network. The hybrid response mechanism improves the reliability of noisy reproductive signal transmission from the brain to the pituitary.
authors.affiliation: Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Frederique
authors.initials: F
authors.lastname: Ruf
authors.forename: Myung-June
authors.initials: MJ
authors.lastname: Park
authors.forename: Fernand
authors.initials: F
authors.lastname: Hayot
authors.forename: Gang
authors.initials: G
authors.lastname: Lin
authors.forename: Badrinath
authors.initials: B
authors.lastname: Roysam
authors.forename: Yongchao
authors.initials: Y
authors.lastname: Ge
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Sealfon
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D051766:Early Growth Response Protein 1 / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000737:chemistry*; D051379:Mice; D008856:Microscopy, Fluorescence; D008962:Models, Theoretical; D010766:Phosphorylation; D010902:Pituitary Gland / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D012333:RNA, Messenger; D007987:Gonadotropin-Releasing Hormone; D048049:Extracellular Signal-Regulated MAP Kinases