D ₂ dopamine receptors induce mitogen-activated protein kinase and cAMP response element-binding protein phosphorylation in neurons

Abstract

The dopamine system plays a significant role in motor function and associative learning (1, 2). Dysfunction in dopamine signaling has been implicated in many neuropsychiatric disorders, such as Parkinson's disease, schizophrenia, attention deficit hyperactivity disorder, and drug abuse. One mechanism that underlies the dopaminergic regulation of cellular physiology involves modulation of ion channel activity and associated short-term changes in cellular excitability (3-6). Another mechanism involves regulation of gene expression, which can produce long-term changes in synaptic plasticity (7,8).Dopamine acts through the D 1 and D 2 subfamilies of G-protein-coupled receptors. Many antipsychotic drugs, which are D 2 receptor antagonists, can induce gene expression (9), suggesting that D 2 receptors, like D 1 receptors (10-12), are important in gene regulation. Previous studies have shown that D 1 and D 2 dopamine receptors synergistically activate immediate early gene expression and locomotion in dopaminedepleted striatum (13,14). This D 1 -D 2 synergy indicates that D 2 receptors may achieve these effects through mechanisms other than that of reducing cAMP formation. One such possible mechanism is to elevate intracellular calcium (15).Two potential targets for D 2 receptors are the mitogenactivated protein kinase (MAPK) and the cAMP response element-binding protein (CREB). MAPKs are a family of serine͞threonine kinases that regulate multiple cellular responses including gene expression, and many MAPK substrates are transcription factors (16). The extracellular signalregulated MAPK (ERK) is phosphorylated at Thr202͞Tyr204 by a wide variety of stimuli, such as Ca 2ϩ , growth factors, and neurotransmitters (17-19). CREB is a plasticity-associated transcription factor that regulates the expression of many downstream genes containing CRE elements, such as c-fos (20,21). CREB is phosphorylated at Ser-133 by multiple protein kinases, including protein kinase A (PKA) and Ca 2ϩ ͞calmod-ulin-dependent protein kinases II and IV (CaMK) (22)(23)(24). In the present study, we provide evidence that D 2 receptors can regulate gene expression by coupling to the Gq͞PLC␤ pathway, causing an elevation of intracellular Ca 2ϩ and activation of PKC, leading to the phosphorylation and activation of MAPK and CREB. Because MAPK and CREB signaling cascades are critical for neuronal plasticity and memory formation (25), our results provide a possible mechanism for long-term actions of D 2 receptors. MATERIALS AND METHODSPreparation and Treatment of Brain Slices. Four-week-old male Sprague-Dawley rats or C57BL͞6J mice were anesthetized and decapitated. Brains were quickly removed, iced, and blocked for slicing. Sagital sections (400 m) of the brain (cerebellum removed) were cut with a Vibratome Technical Products International (St. Louis). The major brain areas in the slices included neocortex, striatum, hippocampus, thalamus, and substantia nigra. The slices were bathed in a low Ca 2ϩ Hepes-buffered salt solution [in mM: 140 Na isothionate, ...

cAMP-dependent Protein Kinase Induces cAMP-response Element-binding Protein Phosphorylation via an Intracellular Calcium Release/ERK-dependent Pathway in Striatal Neurons

“…In agreement with this latter hypothesis, in the present study we have found that activation of the cAMP/PKA-dependent pathway leads to activation of the tyrosine kinase PYK2 (25). This is consistent with the observation that, in striatal brain slices, stimulation of D 2 receptors induces tyrosine phosphorylation of PYK2 via a phospholipase C-mediated intracellular Ca 2ϩ release (37). So far, it is still unclear whether in striatum activation of PYK2 is implicated in CREB phosphorylation, because D 2 -dependent CREB phosphorylation was not blocked by the broad spectrum tyrosine kinase inhibitor genistein (37).…”

Oxidative Stress ActivatesFUS1andRLM1Transcription in the YeastSaccharomyces cerevisiaein an Oxidant-dependent Manner

“…It also has been suggested that l-dopa as well as dopamine stimulate the MAPK activity of the classical extracellular signal-regulated kinase (ERK) pathway in neuronally derived cultured PC12 cells (Yan et al, 1999;Koshimura et al, 2000). The yeast pheromone pathway has been suggested to be an orthologue of the classical mammalian ERK pathway (Caffrey et al, 1999).…”

BDNF Protects the Neonatal Brain from Hypoxic-Ischemic InjuryIn Vivovia the ERK Pathway

“…In light of this, it is interesting to note that stimulation of neurotransmitter receptors such as muscarinic acetylcholine receptors results in prolonged activation of ERK1/2 both in vitro and in vivo (Rosenblum et al, 2000). A variety of agents such as ligands for specific neurotransmitter receptors (Ferraguti et al, 1999;Hayashi et al, 1999;Mukherjee et al, 1999;Yan et al, 1999), nitric oxide (Yun et al, 1998), and estrogen (Singh et al, 1999) can activate the neuronal ERK pathway in vitro. A search for agents that can activate the ERK pathway or its downstream mediators in neurons in vivo seems warranted to attempt to develop better therapies against neonatal H-I brain injury.…”