Activation of Protein Kinase G After Repeated Cocaine Administration Is Necessary for the Phosphorylation of α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptor GluA1 at Serine 831 in the Rat Nucleus Accumbens.

Ju Hwan Yang,Dong Kun Lee,Eun Sang Choe,Jeong Hwan Oh,Yeonhee Ryu,In Soo Ryu,Su Yeon Seo,Jieun Kim

doi:10.3389/fnmol.2018.00263

Abstract

Phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the striatum plays a crucial role in regulating the receptor-coupled signaling cascades leading to behavioral changes associated with psychostimulant exposure. The present study determined if activation of protein kinase G (PKG) contributes to the phosphorylation of AMPA receptor GluA1 subunit at the position of serine 831 (GluA1-S831) in the rat nucleus accumbens (NAc) after repeated cocaine administration. The results demonstrated that repeated intraperitoneal (i.p.) injections of cocaine (20 mg/kg) once a day for seven consecutive days significantly increased the level of phosphorylated (p)GluA1-S831. This increase was decreased by the intra-NAc infusion of either the cyclic guanosine monophosphate (cGMP) analog, Rp-8-Br-PET-cGMPS (5 nmol/1 μL), or the PKG inhibitor, KT5823 (2 nmol/1 μL). Repeated cocaine administration increased PKG binding activity to GluA1. This increase in GluA1-S831 phosphorylation after repeated cocaine administration was decreased by the intra-NAc infusion of the synthetic peptide (Tat-tagged interfering peptide (Tat-GluA1-i)), that interferes with the binding of PKG to GluA1. Intra-NAc infusion of the interfering peptide also reduced the repeated cocaine-induced increase in locomotor activity. These findings suggest that activated PKG, after repeated exposure to cocaine, binds to AMPA receptor GluA1 and is required for the phosphorylation of S831, contributing to behavioral changes.

Highlights

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor is an ionotropic glutamate receptor that plays a crucial role in drug-mediated synaptic plasticity by regulating fast ion conductance (Bowers et al, 2010; Oh et al, 2013; Hanley, 2014)
It is known that serine residue 831 (S831) is phosphorylated by protein kinase C (PKC) and calmodulin-dependent protein kinase II (CaMKII), while serine 845 (S845) is phosphorylated by protein kinase A (PKA) in transfected cells expressing GluA1 and protein kinase G (PKG) in the hippocampus and hippocampal primary cultured neurons (Roche et al, 1996; Mammen et al, 1997; Serulle et al, 2007). These findings suggest that phosphorylation sites on the two serine residues in GluA1 subunit are associated with glutamate and/or dopamine receptor-coupled protein kinase activity after cocaine administration
This study was performed to determine whether repeated cocaine administration phosphorylates GluA1-S831 because it phosphorylates GluA1-S845 in the nucleus accumbens (NAc) (Seo et al, 2013)

Summary

Introduction

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor is an ionotropic glutamate receptor that plays a crucial role in drug-mediated synaptic plasticity by regulating fast ion conductance (Bowers et al, 2010; Oh et al, 2013; Hanley, 2014). Phosphorylation of S845 regulates open probability and open duration of AMPA receptors via PKA activation coupled to dopamine D1 receptors (Banke et al, 2000; Han and Whelan, 2009), while phosphorylation of S831 regulates AMPA conductance via CaMKII or PKC activation coupled with glutamate receptors (Derkach et al, 1999; Jenkins and Traynelis, 2012). In addition to single phosphorylation of the receptors, dual phosphorylation of S831 and S845 regulates membrane trafficking of AMPA receptors and synaptic insertion (Gao et al, 2006; Derkach et al, 2007). These findings suggest that phosphorylation of the serine residue contributes to the alternation of AMPA receptor functions

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