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The Journal of Neuroscience, April 13, 2005, 25(15):3763-3773; doi:10.1523/JNEUROSCI.4574-04.2005

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Cellular/Molecular
Metabotropic Glutamate Receptors and Dopamine Receptors Cooperate to Enhance Extracellular Signal-Regulated Kinase Phosphorylation in Striatal Neurons

Pamela J. Voulalas,¹ Lynne Holtzclaw,² Jennifer Wolstenholme,¹ James T. Russell,² and Steven E. Hyman¹

¹Molecular Plasticity Section, National Institute of Neurological Disorders and Stroke, and ²Section on Cell Biology and Signal Transduction, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892

Striatal medium spiny neurons are an important site of convergence for signaling mediated by the neurotransmitters dopamine and glutamate. We report that in striatal neurons in primary culture, signaling through group I metabotropic glutamate receptors (mGluRs) 1/5 and the D₁ class of dopamine receptors (DRs) 1/5 converges to increase phosphorylation of the mitogen-activated protein kinase ERK2 (extracellular signal-regulated kinase 2). Induction of mitogen-activated protein kinase kinase-dependent signaling cascades by either mGluR1/5 or DR1/5 gave rise to increases in phosphorylation of ERK2. Coactivation of mGluR1/5 and DR1/5 with (S)-3,5-dihydroxyphenylglycine and (+)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride enhanced the phosphorylation of ERK2. This interaction between mGluR1/5 and DR1/5 required protein kinase C (PKC), because the PKC inhibitors calphostin C, bisindolylmaleimide I, and Gö6976 blocked DR1/5-enhanced phosphorylation of ERK2. Use of the phosphatase inhibitors calyculin and okadaic acid indicated that inhibition of protein phosphatases 1 and 2A dramatically enhanced ERK2 phosphorylation by mGluR1/5. Coactivation of mGluR1/5 and DR1/5 also enhanced cAMP-response element binding protein (CREB) phosphorylation (compared with each receptor agonist alone) but did not enhance CREB-mediated transcriptional activity. Thus, signal transduction pathways activated by DR1/5 and mGluR5 interact to modify downstream events in striatal neurons while retaining numerous regulatory checkpoints.

Key words: metabotropic glutamate receptor; dopamine receptor; ERK; PKC; striatum; signal transduction

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Received Nov 8, 2004; revised February 24, 2005; accepted February 28, 2005.

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