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Adenosine A 2A receptors are required for glutamate mG luR5‐ and dopamine D1 receptor‐evoked ERK 1/2 phosphorylation in rat hippocampus: involvement of NMDA receptor
Author(s) -
Krania Paraskevi,
Dimou Eleni,
Bantouna Maria,
Kouvaros Stylianos,
Tsiamaki Eirini,
Papatheodoropoulos Costas,
Sarantis Konstantinos,
Angelatou Fevronia
Publication year - 2018
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14268
Subject(s) - nmda receptor , metabotropic glutamate receptor 5 , metabotropic glutamate receptor , glutamate receptor , metabotropic receptor , mapk/erk pathway , phosphorylation , neuroscience , long term depression , long term potentiation , chemistry , adenosine , microbiology and biotechnology , hippocampal formation , synaptic plasticity , hippocampus , stimulation , biology , receptor , endocrinology , ampa receptor , biochemistry
Interaction between mGluR5 and NMDA receptors ( NMDAR ) is vital for synaptic plasticity and cognition. We recently demonstrated that stimulation of mGluR5 enhances NMDAR responses in hippocampus by phosphorylating NR2B(Tyr1472) subunit, and this reaction was enabled by adenosine A 2A receptors (A 2A R) (J Neurochem, 135, 2015, 714). In this study, by using in vitro phosphorylation and western blot analysis in hippocampal slices of male Wistar rats, we show that mGluR5 stimulation or mGluR5/ NMDAR s co‐stimulation synergistically activate ERK 1/2 signaling leading to c‐Fos expression. Interestingly, both reactions are under the permissive control of endogenous adenosine acting through A 2A Rs. Moreover, mGluR5‐mediated ERK 1/2 phosphorylation depends on NMDAR , which however exhibits a metabotropic way of function, since no ion influx through its ion channel is required. Furthermore, our results demonstrate that mGluR5 and mGluR5/ NMDAR ‐evoked ERK 1/2 activation correlates well with the mGluR5/ NMDAR ‐evoked NR2B(Tyr1472) phosphorylation, since both phenomena coincide temporally, are Src dependent, and are both enabled by A 2A Rs. This indicates a functional involvement of NR2B(Tyr1472) phosphorylation in the ERK 1/2 activation. Our biochemical results are supported by electrophysiological data showing that in CA 1 region of hippocampus, the theta burst stimulation (TBS)‐induced long‐term potentiation coincides temporally with an increase in ERK 1/2 activation and both phenomena are dependent on the tripartite A 2A , mGlu5, and NMDAR s. Furthermore, we show that the dopamine D1 receptors evoked ERK 1/2 activation as well as the NR2B(Tyr1472) phosphorylation are also regulated by endogenous adenosine and A 2A Rs. In conclusion, our results highlight the A 2A Rs as a crucial regulator not only for NMDAR responses, but also for regulating ERK 1/2 signaling and its downstream pathways, leading to gene expression, synaptic plasticity, and memory consolidation.