GABAA receptor-associated phosphoinositide 3-kinase is required for insulin-induced recruitment of postsynaptic GABAA receptors.
Type A gamma-aminobutyric acid (GABAA) receptors mediate most of the fast inhibitory synaptic transmission within the vertebrate brain. The regulation of this inhibition is vital in modulating neural activity. One regulator of GABAA receptor function is insulin, which can serve to enhance GABAA receptor-mediated miniature inhibitory postsynaptic currents, via an increase in the number of receptors at the plasma membrane. We set out to investigate the molecular mechanisms involved in the insulin-induced potentiation of GABAA receptor-mediated responses, by examining the role of phosphoinositide 3-kinase (PI3-K), a key mediator of the insulin response within the brain. We found that PI3-K associates with the GABAA receptor, and this interaction is increased following insulin treatment. Additionally, the beta2 subunit of the GABAA receptor appears to mediate the insulin-stimulated association with the N-terminal SH2 domain of the p85 subunit of PI3-K. Our results imply a mechanism whereby insulin can regulate changes in synaptic transmission through its downstream actions on the GABAA receptor.
Vetiska
S M
SM
Programme in Brain and Behavior Research, Hospital for Sick Children and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
Ahmadian
G
G
Ju
W
W
Liu
L
L
Wymann
M P
MP
Wang
Y T
YT
D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006624:Hippocampus / Q000166:cytology; D047468:Immunoprecipitation / Q000379:methods; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
D004791:Enzyme Inhibitors; D007328:Insulin; D021122:Protein Subunits; D011963:Receptors, GABA-A; D019869:Phosphatidylinositol 3-Kinases