Neurotransmitter regulation of MAP kinase signaling in striatal neurons in primary culture

Abstract

Glutamate and dopamine are important neurotransmitters in the basal ganglia. Dopamine can act via D1 receptors to activate adenylyl cyclase in striatal neurons, while glutamate stimulation of NMDA receptors leads to an increase in intracellular calcium. Increases in intracellular calcium or cAMP can induce immediate early gene expression in striatal neurons. In the present study, NMDA receptor stimulation or adenylyl cyclase activation resulted in the activation of MAP kinase in striatal neurons in primary culture. The effect of cAMP appeared to involve cAMP-dependent protein kinase, in addition to a tyrosine kinase and MEK. NMDA-induced MAP kinase activation was also dependent on a tyrosine kinase and MEK. The EGF receptor, which has been implicated in calcium- and G protein-induced MAP kinase activation, did not mediate the effects of NMDA or forskolin on MAP kinase. Furthermore, the src kinase inhibitor, herbimycin A, and the phosphoinositol-3-kinase inhibitor, wortmannin, did not prevent MAP kinase activation by these stimuli. However, the ability of both NMDA and forskolin to activate MAP kinase in striatal neurons was blocked by SB 203580, an inhibitor of p38 reactivating kinase. These results indicate that both NMDA receptor activation and elevations in cAMP can result in MEK-induced MAP kinase activation in striatal neurons. However, the signal transduction pathways mediating these responses appear to be distinct from those known to mediate MAP kinase activation by other stimuli.

5-Hydroxytryptamine4Receptor Activation of the Extracellular Signal-regulated Kinase Pathway Depends on Src Activation but Not on G Protein or β-Arrestin Signaling

“…These data do not indicate that cAMP is not able to stimulate ERK activation in neurons but only that activation of ERK by 5-HT 4 Rs is mostly cAMP/PKA independent. Indeed, activation of ERKs via a cAMP route is known to occur in several cells, such as primary neurons in culture (Vincent et al, 1998), PC12 cells, melanocytes, and thyroid cells, and it generally occurs via a B-Raf-MEK pathway (Dumaz and Marais, 2005). In contrast, in many other cells, cAMP inhibits ERK via inhibition of C-Raf, which leads to the well-known antiproliferate effects of cAMP (Dumaz and Marais, 2005).…”

Glutamate Promotes Proliferation of Striatal Neuronal Progenitors by an NMDA Receptor-Mediated Mechanism

“…Both NMDA and non-NMDA ionotropic receptors are widely expressed in the prenatal rat telencephalon and exhibit developmentally regulated patterns of subunit expression that determine distinct functional effects (Misgeld and Dietzel, 1989;Monyer et al, 1994;Landwehrmeyer et al, 1995;Wullner et al, 1997;Nansen et al, 2000). In vitro, cells derived from the LGE exhibit NMDA responses (Vincent et al, 1998). Here, we provide evidence for NR1 and NR2 subunits in proliferating neuroblasts, suggesting a role for a functional channel in the observed events.…”

“…With respect to classical neurotransmitter effects, proliferation in cortical progenitors after muscarinic receptor activation appears to be mediated by phosphatidylinositol-3-kinase (PI3) and ERK signaling pathways (Li et al, 2001). NMDA receptor activation in striatal neurons has been demonstrated to initiate this pathway in a PI3-dependent manner (Vincent et al, 1998;Schwarszschild et al, 1999;Perkinton et al, 2002). Components of this cascade (e.g., CaM-kinase, Ras, Mek, ERK1/2, and PI3) can be localized to glutamatergic postsynaptic densities (Husi et al, 2000).…”

Appetitive cue-evoked ERK signaling in the nucleus accumbens requires NMDA and D1 dopamine receptor activation and regulates CREB phosphorylation

“…Second, stimulation of glutamatergic afferents in striatal slices (Sgambato et al 1998a, b;Vanhoutte et al 1999) or bath-application of glutamate or NMDA to striatal neurons in culture (Vincent et al 1998;Schwarzschild et al 1999;Fuller et al 2001;Perkinton et al 2002;Mao et al 2004) caused increases in striatal ERK activation. Third, NMDAR antagonists were found to interfere with glutamate-, D1R-, or drug-evoked ERK activation in the striatum (Vincent et al 1998;Valjent et al 2000;Mazzucchelli et al 2002;Haberny and Carr 2005;Jenab et al 2005;Jiao et al 2007;Fasano et al 2009;Pascoli et al 2011). Our data showing that NMDAR blockade interferes with CS-evoked ERK activation in the NAc extend these findings by demonstrating a role for NMDAR activation in accumbal ERK signaling by behaviorally relevant cues as well.…”