title: A-kinase anchoring protein-calcineurin signaling in long-term depression of GABAergic synapses.
abstract: The postsynaptic scaffolding A-kinase anchoring protein 79/150 (AKAP79/150) signaling complex regulates excitatory synaptic transmission and strength through tethering protein kinase A (PKA), PKC, and calcineurin (CaN) to the postsynaptic densities of neurons (Sanderson and Dell'Acqua, 2011), but its role in inhibitory synaptic transmission and plasticity is unknown. Using immunofluorescence and whole-cell patch-clamp recording in rat midbrain slices, we show that activation of postsynaptic D(2)-like family of dopamine (DA) receptor in the ventral tegmental area (VTA) induces long-term depression (LTD) of GABAergic synapses on DA neurons through an inositol triphosphate receptor-mediated local rise in postsynaptic Ca(2+) and CaN activation accompanied by PKA inhibition, which requires AKAP150 as a bridging signaling molecule. Our data also illuminate a requirement for a clathrin-mediated internalization of GABA(A) receptors in expression of LTD(GABA). Moreover, disruption of AKAP-PKA anchoring does not affect glutamatergic synapses onto DA neurons, suggesting that the PKA-AKAP-CaN complex is uniquely situated at GABA(A) receptor synapses in VTA DA neurons to regulate plasticity associated with GABA(A) receptors. Drug-induced modulation of GABAergic plasticity in the VTA through such novel signaling mechanisms has the potential to persistently alter the output of individual DA neurons and of the VTA, which may contribute to the reinforcing or addictive properties of drugs of abuse.
authors: Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.
authors: Matthieu
authors: M
authors: Dacher
authors: Shawn
authors: S
authors: Gouty
authors: Steven
authors: S
authors: Dash
authors: Brian M
authors: BM
authors: Cox
authors: Fereshteh S
authors: FS
authors: Nugent
mesh_terms: D054758:A Kinase Anchor Proteins / Q000502:physiology*; D000818:Animals; D019703:Calcineurin / Q000502:physiology*; D005260:Female; D059330:GABAergic Neurons / Q000502:physiology*; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D008297:Male; D008636:Mesencephalon / Q000502:physiology; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000502:physiology
chemical_list: D054758:A Kinase Anchor Proteins; C415703:Akap5 protein, rat; D011963:Receptors, GABA-A; D019703:Calcineurin
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