Akt-dependent and isoform-specific regulation of dopamine transporter cell surface expression.
Dopamine (DA) is a neurotransmitter implicated in multiple functions, including movement, cognition, motivation, and reward. The DA transporter (DAT) is responsible for clearing extracellular DA, thereby terminating DA neurotransmission. Previously, it has been shown that insulin signaling through protein kinase B/Akt regulates DAT function by fine-tuning DAT cell surface expression. Importantly, specific Akt isoforms (e.g., Akt1, Akt2) serve distinct physiological functions. Here, we demonstrate using isoform-specific Akt inhibitors that basal activity of Akt2, rather than Akt1, regulates DAT cell surface expression. Since Akt2 activation is mediated by insulin, these data further implicate insulin signaling as an important modulator of DAT function and dopaminergic tone.
Room 7124, Medical Research Building III, Center for Molecular Neuroscience, Nashville, TN, USA.
Nicole K
NK
Speed
Heinrich J G
HJ
Matthies
J Phillip
JP
Kennedy
Roxanne A
RA
Vaughan
Jonathan A
JA
Javitch
Scott J
SJ
Russo
Craig W
CW
Lindsley
Kevin
K
Niswender
Aurelio
A
Galli
D000494:Allosteric Regulation; D000818:Animals; D002462:Cell Membrane / Q000201:enzymology; D003342:Corpus Striatum / Q000166:cytology; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000201:enzymology; D057809:HEK293 Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000502:physiology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D021381:Protein Transport / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D013379:Substrate Specificity; D014162:Transfection
D050483:Dopamine Plasma Membrane Transport Proteins; D007328:Insulin; D007527:Isoenzymes; D011993:Recombinant Fusion Proteins; C494918:AKT1 protein, human; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D004298:Dopamine