title: Insulin reveals Akt signaling as a novel regulator of norepinephrine transporter trafficking and norepinephrine homeostasis.
abstract: Noradrenergic signaling in the CNS plays an essential role in circuits involving attention, mood, memory, and stress as well as providing pivotal support for autonomic function in the peripheral nervous system. The high-affinity norepinephrine (NE) transporter (NET) is the primary mechanism by which noradrenergic synaptic transmission is terminated. Data indicate that NET function is regulated by insulin, a hormone critical for the regulation of metabolism. Given the high comorbidity of metabolic disorders such as diabetes and obesity with mental disorders such as depression and schizophrenia, we sought to determine how insulin signaling regulates NET function and thus noradrenergic homeostasis. Here, we show that acute insulin treatment, through the downstream kinase protein kinase B (Akt), significantly decreases NET surface expression in mouse hippocampal slices and superior cervical ganglion neuron boutons (sites of synaptic NE release). In vivo manipulation of insulin/Akt signaling, with streptozotocin, a drug that induces a type 1-like diabetic state in mice, also results in aberrant NET function and NE homeostasis. Notably, we also demonstrate that Akt inhibition or stimulation, independent of insulin, is capable of altering NET surface availability. These data suggest that aberrant states of Akt signaling such as in diabetes and obesity have the potential to alter NET function and noradrenergic tone in the brain. Furthermore, they provide one potential molecular mechanism by which Akt, a candidate gene for mood disorders such as schizophrenia and depression, can impact brain monoamine homeostasis.
authors.affiliation: Departments of Molecular Physiology and Biophysics, Center for Molecular Neuroscience, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors.forename: Sabrina D
authors.initials: SD
authors.lastname: Robertson
authors.forename: Heinrich J G
authors.initials: HJ
authors.lastname: Matthies
authors.forename: W Anthony
authors.initials: WA
authors.lastname: Owens
authors.forename: Vidiya
authors.initials: V
authors.lastname: Sathananthan
authors.forename: Nicole S Bibus
authors.initials: NS
authors.lastname: Christianson
authors.forename: J Phillip
authors.initials: JP
authors.lastname: Kennedy
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: Lynette C
authors.initials: LC
authors.lastname: Daws
authors.forename: Aurelio
authors.initials: A
authors.lastname: Galli
mesh_terms: D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009638:Norepinephrine / Q000502:physiology*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D007328:Insulin; D050484:Norepinephrine Plasma Membrane Transport Proteins; D051057:Proto-Oncogene Proteins c-akt; D009638:Norepinephrine