Adrenergic modulation of NMDA receptors in prefrontal cortex is differentially regulated by RGS proteins and spinophilin

doi:10.1073/pnas.0604560103

Adrenergic modulation of NMDA receptors in prefrontal cortex is differentially regulated by RGS proteins and spinophilin

*Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14214;
^†Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508; and
^‡Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10021

Edited by Richard L. Huganir, Johns Hopkins University School of Medicine, Baltimore, MD, and approved October 6, 2006 (received for review June 2, 2006)

Abstract

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 α1- and α2-adrenergic receptors (α1-ARs, α2-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 α1-AR or α2-AR agonists also decreased NMDAR-EPSC amplitude and whole-cell NMDAR current amplitude in dissociated PFC neurons. The α1-AR effect depended on the phospholipase C–inositol 1,4,5-trisphosphate–Ca²⁺ pathway, whereas the α2-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 α1-AR on NMDAR currents, whereas only RGS4 was involved in inhibiting α2-AR regulation of NMDAR currents. The regulating effects of RGS2/4 on α1-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 α2-AR signaling was not altered in spinophilin-knockout mice. Our work suggests that activation of α1-ARs or α2-ARs suppresses NMDAR currents in PFC neurons by distinct mechanisms. The effect of α1-ARs is modified by RGS2/4 that are recruited to the receptor complex by spinophilin, whereas the effect of α2-ARs is modified by RGS4 independent of spinophilin.

Footnotes

^§To whom correspondence should be addressed. E-mail: zhenyan{at}buffalo.edu
Author contributions: J.F. and Z.Y. designed research; W.L. and E.Y.Y. performed research; P.B.A. and P.G. contributed new reagents/analytic tools; W.L. analyzed data; and Z.Y. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS direct submission.
Abbreviations:

2APB,

2-aminoethoxydiphenyl borane;

AR,

adrenergic receptor;

EPSC,

excitatory postsynaptic currents;

GPCR,

G protein-coupled receptor;

IP3,

inositol 1,4,5-trisphosphate;

NMDAR,

NMDA receptor;

NR2B,

NMDAR 2B;

PFC,

prefrontal cortex;

PLC,

phospholipase C;

RGS,

regulators of G protein signaling.