Abstract
ObjectiveThe adenosine A1 receptor is a Gαi/o protein‐coupled receptor and inhibits upon activation cAMP formation and protein kinase A (PKA) activity. As a widely expressed receptor in the mammalian brain, A1 receptors are implicated in the modulation of a variety of neuronal and synaptic activities. In this study, we investigated the role of A1 receptors in the regulation of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors in the adult rat brain in vivo.MethodsAdult male Wistar rats were used in this study. After a systemic injection of the A1 antagonist DPCPX, rats were sacrificed and several forebrain regions were collected for assessing changes in phosphorylation of AMPA receptors using Western blots.ResultsA systemic injection of the A1 antagonist DPCPX induced an increase in phosphorylation of AMPA receptor GluA1 subunits at a PKA‐dependent site, serine 845 (S845), in the two subdivisions of the striatum, the caudate putamen, and nucleus accumbens. DPCPX also increased S845 phosphorylation in the medial prefrontal cortex (mPFC) and hippocampus. The DPCPX‐stimulated S845 phosphorylation was a transient and reversible event. Blockade of Gαs/olf‐coupled dopamine D1 receptors with a D1 antagonist SCH23390 abolished the responses of S845 phosphorylation to DPCPX in the striatum, mPFC, and hippocampus. DPCPX had no significant impact on phosphorylation of GluA1 at serine 831 and on expression of total GluA1 proteins in all forebrain regions surveyed.ConclusionThese data demonstrate that adenosine A1 receptors maintain an inhibitory tone on GluA1 S845 phosphorylation under normal conditions. Blocking this inhibitory tone leads to the upregulation of GluA1 S845 phosphorylation in the striatum, mPFC, and hippocampus via a D1‐dependent manner.
Highlights
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor is widely expressed in the mammalian brain and is actively involved in the regulation of a variety of cellular and synaptic activities (Bernard, Somogyi, & Bolam, 1997; Kondo, Okabe, Sumino, & Okado, 2000; Reimers, Milovanovic, & Wolf, 2011)
We found that an A1 receptor antagonist DPCPX increased phosphorylation of AMPA receptor GluA1 subunits in the key limbic reward regions, including the striatum, medial prefrontal cortex, and hippocampus
We investigated the effect of an A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) on GluA1 phosphorylation at serine 845 (S845) and serine 831 (S831) sites in different brain regions, including the caudate putamen (CPu), nucleus accumbens (NAc), medial prefrontal cortex, and hippocampus
Summary
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor is widely expressed in the mammalian brain and is actively involved in the regulation of a variety of cellular and synaptic activities (Bernard, Somogyi, & Bolam, 1997; Kondo, Okabe, Sumino, & Okado, 2000; Reimers, Milovanovic, & Wolf, 2011). Consistent evidence shows that pharmacological activation of Gαs/olf-coupled D1 receptors by the direct or indirect D1 agonists upregulated GluA1 phosphorylation at the PKA site (S845) in the striatum, probably via a signaling mechanism involving the cAMP/PKA pathway (Chao, Lu, Lee, Huganir, & Wolf, 2002; Mao, Diaz, Fibuch, & Wang, 2013; Price, Kim, & Raymond, 1999; Snyder et al, 2000; Swayze, Lise, Levinson, Phillips, & El-Husseini, 2004; Xue et al, 2014, 2017). A1 and A2A subtypes are primarily expressed (Sheth et al, 2014) The former is coupled to Gαi/o proteins, whereas the latter is coupled to Gαs/olf proteins. We tested the effect of DPCPX on GluA1 phosphorylation in the presence of a dopamine D1 antagonist SCH23390
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