Abstract
There is increasing evidence that extracellular cGMP modulates glutamatergic neurotransmission and some forms of learning. However, the underlying mechanisms remain unknown. We proposed the hypotheses that extracellular cGMP may regulate membrane expression of AMPA receptors. To do this extracellular cGMP should act on a membrane protein and activate signal transduction pathways modulating phosphorylation of the GluA1 and/or GluA2 subunits. It has been shown that extracellular cGMP modulates glycine receptors. The aims of this work were to assess: 1) whether extracellular cGMP modulates membrane expression of GluA1 and GluA2 subunits of AMPA receptors in cerebellum in vivo; 2) whether this is mediated by glycine receptors; 3) the role of GluA1 and GluA2 phosphorylation and 4) identify steps of the intracellular pathways involved. We show that extracellular cGMP modulates membrane expression of GluA1 and GluA2 in cerebellum in vivo and unveil the mechanisms involved. Extracellular cGMP reduced glycine receptor activation, modulating cAMP, protein kinases and phosphatases, and GluA1 and GluA2 phosphorylation, resulting in increased GluA1 and reduced GluA2 membrane expression. Extracellular cGMP therefore modulates membrane expression of AMPA receptors and glutamatergic neurotransmission. The steps identified may be therapeutic targets to improve neurotransmission and neurological function in pathological situations with abnormal glutamatergic neurotransmission.
Highlights
A key mechanism modulating membrane expression is phosphorylation[10]
We analyzed the effects of continuous intracerebral administration of cGMP, which does not cross the cell membrane[22], on membrane expression of GluA1 and GluA2 in cerebellum
Chronic administration of extracellular cGMP induced opposite effects on membrane expression of the subunits of AMPA receptor, increasing GluA1 to 155 ± 18% (p < 0.01) of basal (Fig. 1A) and decreasing (p < 0.05) GluA2 to 69 ± 12% (Fig. 1B and C)
Summary
A key mechanism modulating membrane expression is phosphorylation[10]. Phosphorylation of GluA2 at Ser[880] by protein kinase C (PKC) results in rapid internalization of GluA2-containing AMPA receptor[11,12,13,14]. PKA, in turn, phosphorylates inhibitor-1 (I-1) at Thr[35] which reduces protein phosphatase 1 (PP1) increasing CaMKII phosphorylation and activity[19] These pathways may be induced by different physiological or pathological molecules such as TNF-a9 or NMDA receptor activation by glutamate[19]. Extracellular cGMP at nanomolar concentrations reduces glycine receptors activation in Purkinje neurons, modulating intracellular calcium and CaMKII activity[28]. Chronic intracerebral administration of extracellular cGMP normalized extracellular cGMP in cerebellum of hyperammonemic rats and restored their ability to learn the Y maze task[28] These few reports support the idea that extracellular cGMP, at physiological concentrations, modulates different aspects of the cerebellum function in vivo, as well as some forms of learning (Y maze task) modulated by the cerebellum. We decided to focus the present work in cerebellum
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