title: Glutamate Receptor Modulation Is Restricted to Synaptic Microdomains.
abstract: A diverse array of neuromodulators governs cellular function in the prefrontal cortex (PFC) via the activation of G-protein-coupled receptors (GPCRs). However, these functionally diverse signals are carried and amplified by a relatively small assortment of intracellular second messengers. Here, we examine whether two distinct Gαi-coupled neuromodulators (norepinephrine and GABA) act as redundant regulators of glutamatergic synaptic transmission. Our results reveal that, within single dendritic spines of layer 5 pyramidal neurons, alpha-2 adrenergic receptors (α2Rs) selectively inhibit excitatory transmission mediated by AMPA-type glutamate receptors, while type B GABA receptors (GABA(B)Rs) inhibit NMDA-type receptors. We show that both modulators act via the downregulation of cAMP and PKA. However, by restricting the lifetime of active Gαi, RGS4 promotes the independent control of these two distinct target proteins. Our findings highlight a mechanism by which neuromodulatory microdomains can be established in subcellular compartments such as dendritic spines.
authors.affiliation: Department of Neurobiology, Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Lur
authors.affiliation: Department of Neurobiology, Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address: m.higley@yale.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Higley
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D049229:Dendritic Spines / Q000737:chemistry / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D019706:Excitatory Postsynaptic Potentials; D044385:GTP-Binding Protein alpha Subunits / Q000737:chemistry / Q000378:metabolism; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D036641:Microscopy, Fluorescence, Multiphoton; D009638:Norepinephrine / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000378:metabolism*; D020710:RGS Proteins / Q000378:metabolism; D018091:Receptors, AMPA / Q000737:chemistry / Q000378:metabolism; D017470:Receptors, Glutamate / Q000737:chemistry / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D044385:GTP-Binding Protein alpha Subunits; D020710:RGS Proteins; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C098799:RGS4 protein; D005680:gamma-Aminobutyric Acid; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D009638:Norepinephrine