Metabotropic mGlu5 receptors regulate adenosine A2A receptor signaling

AUTOR(ES)

Nishi, Akinori

FONTE

The National Academy of Sciences

RESUMO

Dopamine, by activating dopamine D1-type receptors, and adenosine, by activating adenosine A2A receptors, stimulate phosphorylation of DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of Mr 32,000) at Thr-34. In this study, we investigated the effect of metabotropic glutamate (mGlu) receptors on DARPP-32 phosphorylation at Thr-34 in neostriatal slices. A broad-spectrum mGlu receptor agonist, trans-ACPD, and a group I mGlu receptor agonist, DHPG, stimulated DARPP-32 phosphorylation at Thr-34. Studies with mGlu receptor antagonists revealed that the effects of trans-ACPD and DHPG were mediated through activation of mGlu5 receptors. The action of mGlu5 receptors required activation of adenosine A2A receptors by endogenous adenosine. Conversely, the action of adenosine A2A receptors required activation of mGlu5 receptors by endogenous glutamate. Coactivation of mGlu5 and adenosine A2A receptors by exogenous agonists synergistically increased DARPP-32 phosphorylation. mGlu5 receptors did not require activation of dopamine D1-type receptors by endogenous dopamine, nor did dopamine D1-type receptors require activation of mGlu5 receptors by endogenous glutamate. DHPG potentiated the effect of forskolin, but not that of 8-bromo-cAMP, and stimulated DARPP-32 phosphorylation in the presence of the phosphodiesterase inhibitor IBMX, suggesting that mGlu5 receptors stimulate the rate of cAMP formation coupled to adenosine A2A receptors. The action of mGlu5 receptors was attenuated by inhibitors of extracellular signal-regulated kinase, but not by inhibitors of phospholipase C, p38, casein kinase 1, or Cdk5. The results demonstrate that mGlu5 receptors potentiate adenosine A2A/DARPP-32 signaling by stimulating the adenosine A2A receptor-mediated formation of cAMP in an extracellular signal-regulated kinase-dependent manner.

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