Upregulation of AMPA receptor GluA1 phosphorylation by blocking adenosine A₁ receptors in the male rat forebrain

Abstract

Objective The 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. Methods Adult 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. Results A 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. Conclusion These 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.

miR-429-3p mediates memory decline by targeting MKP-1 to reduce surface GluA1-containing AMPA receptors in a mouse model of Alzheimer's disease

“…In addition, hyperphosphorylation of GluA1 S831 does not affect AMPAR-trafficking-vesicle transport speed, but causes more vesicles to pause 63 . Disruption of GluA1 phosphorylation, especially at site of S831 29 , 64 , 65 , inhibits the increase in GluA1 number and GluA1 exocytosis frequency in both postsynaptic and extrasynaptic membranes 66 . Combined with the latest research advances, our results suggest that miR-429-3p –MKP-1–ERK1/2-mediated hyperphosphorylation of GluA1 S831 disrupts its normal trafficking, thereby reducing the surface expression of GluA1 in AD.…”

The Signaling Pathways Involved in the Anticonvulsive Effects of the Adenosine A1 Receptor

“…A 1 Rs maintain an inhibitory tone on Ser845 phosphorylation by inhibiting AC in several regions of the rat brain. Inhibition of A 1 R signaling under basal adenosine concentrations increases Ser845 phosphorylation and potentiates AMPAR currents while selective A 1 R activation reduces AMPAR currents in hippocampal slices [ 161 , 162 ]. Furthermore, it was also reported that A 1 Rs decrease the agonist affinity of AMPARs [ 162 ].…”