An investigation into signal transduction mechanisms involved in insulin-induced long-term depression in the CA1 region of the hippocampus.
Recent work has demonstrated that brief application of insulin to hippocampal slices can induce a novel form of long-term depression (insulin-LTD) in the CA1 region of the hippocampus; however, the molecular details of how insulin triggers LTD remain unclear. Using electrophysiological and biochemical approaches in the hippocampal slices, we show here that insulin-LTD (i) is specific to 3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor- but not NMDA receptor-mediated synaptic transmission; (ii) is induced and expressed postsynaptically but does not require the activation of ionotropic and metabotropic glutamate receptors; (iii) requires a concomitant Ca(2+) influx through l-type voltage-activated Ca(2+) channels (VACCs) and the release of Ca(2+) from intracellular stores; (iv) requires the series of protein kinases, including protein tyrosine kinase (PTK), phosphatidylinositol 3-kinase (PI3K), and protein kinase C (PKC); (v) is mechanistically distinct from low-frequency stimulation-induced LTD (LFS-LTD) and independent on protein phosphatase 1/2 A (PP1/2 A) and PP2B activation; (vi) is dependent on a rapamycin-sensitive local translation of dendritic mRNA, and (vii) is associated with a persistent decrease in the surface expression of GluR2 subunit. These results suggest that a PI3K/PKC-dependent insulin signaling, which controls postsynaptic surface AMPA receptor numbers through PP-independent endocytosis, may be a major expression mechanism of insulin-LTD in hippocampal CA1 neurons.
Huang
Chiung-Chun
CC
Department of Pharmacology, National Cheng Kung University, Tainan, Taiwan.
Lee
Cheng-Che
CC
Hsu
Kuei-Sen
KS
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism; D004558:Electric Stimulation; D004705:Endocytosis / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology*; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology*; D036881:Long-Term Synaptic Depression / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D054645:Protein Phosphatase 1; D021122:Protein Subunits / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D007328:Insulin; D021122:Protein Subunits; D011500:Protein Synthesis Inhibitors; D018091:Receptors, AMPA; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C104722:glutamate receptor ionotropic, AMPA 2; D002118:Calcium; D020123:Sirolimus