Liu W, Yuen EY, Allen PB, Feng J, Greengard P, Yan Z. Adrenergic modulation of NMDA receptors in prefrontal cortex is differentially regulated by RGS proteins and spinophilin. Proc Natl Acad Sci USA 103: 18338-18343

Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14214, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 12/2006; 103(48):18338-43. DOI: 10.1073/pnas.0604560103
Source: PubMed


The noradrenergic system in the prefrontal cortex (PFC) is involved in many physiological and psychological processes, including working memory and mood control. To understand the functions of the noradrenergic system, we examined the regulation of NMDA receptors (NMDARs), key players in cognition and emotion, by alpha1- and alpha2-adrenergic receptors (alpha1-ARs, alpha2-ARs) in PFC pyramidal neurons. Applying norepinephrine or a norepinephrine transporter inhibitor reduced the amplitude but not paired-pulse ratio of NMDAR-mediated excitatory postsynaptic currents (EPSC) in PFC slices. Specific alpha1-AR or alpha2-AR agonists also decreased NMDAR-EPSC amplitude and whole-cell NMDAR current amplitude in dissociated PFC neurons. The alpha1-AR effect depended on the phospholipase C-inositol 1,4,5-trisphosphate-Ca(2+) pathway, whereas the alpha2-AR effect depended on protein kinase A and the microtubule-based transport of NMDARs that is regulated by ERK signaling. Furthermore, two members of the RGS family, RGS2 and RGS4, were found to down-regulate the effect of alpha1-AR on NMDAR currents, whereas only RGS4 was involved in inhibiting alpha2-AR regulation of NMDAR currents. The regulating effects of RGS2/4 on alpha1-AR signaling were lost in mutant mice lacking spinophilin, which binds several RGS members and G protein-coupled receptors, whereas the effect of RGS4 on alpha2-AR signaling was not altered in spinophilin-knockout mice. Our work suggests that activation of alpha1-ARs or alpha2-ARs suppresses NMDAR currents in PFC neurons by distinct mechanisms. The effect of alpha1-ARs is modified by RGS2/4 that are recruited to the receptor complex by spinophilin, whereas the effect of alpha2-ARs is modified by RGS4 independent of spinophilin.

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    • "b 2 AR activation also stimulates PKA-mediated spinophilin phosphorylation to increase a 2A AR endocytosis (Cottingham et al., 2013). Conversely, spinophilin appears to promote RGS2-mediated inhibition of a 2 AR-evoked Ca 21 signaling and RGS2-mediated modulation of a 1 -adrenergic receptor–NMDAR crosstalk (Wang et al., 2005; Liu et al., 2006). In spinophilin knockout mice, the a 2A adrenergic receptor (a 2A AR) exhibits increased G protein coupling and sensitized responses to a 2A AR agonists (Lu et al., 2010; Cottingham et al., 2012). "
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    • "In fact, NE has a variety of effects at alpha-as well as beta-receptors in central neurons. Previous studies indicate that NE at 10–20 lM range consistently decreases alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA)-induced current (Dinh et al., 2009), AMPA–EPSC (Law-Tho et al., 1993; Kobayashi, 2007; Kobayashi et al., 2009), or N-methyl- D-aspartate (NMDA)–EPSC (Liu et al., 2006) via either postsynaptic activation of alpha-1 receptor in the PFC or presynaptic alpha-2 receptor in amygdala (Delaney et al., 2007), or even postsynaptic alpha-2 receptor in PFC (Ji et al., 2008b). Whatever the receptor-specificity and pre-or postsynaptic action, the consistent finding of a depressive effect of NE on excitatory synaptic transmission is contradictory to the insignificant effect of NE in P–P monosynaptic connections as observed in the current study. "
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