Extracellular Signal-Regulated Kinase (ERK) Controls Immediate Early Gene Induction on Corticostriatal Stimulation

Abstract

Activity-dependent changes in neuronal structure and synaptic remodeling depend critically on gene regulation. In an attempt to understand how glutamate receptor stimulation at the membrane leads to gene regulation in the nucleus, we traced intracellular signaling pathways targeting DNA regulatory elements of immediate early genes (IEGs). For this purpose we used an in vivo electrical stimulation of the glutamatergic corticostriatal pathway. We show that a transient activation of extracellular signal-regulated kinase (ERK) proteins (detected by immunocytochemistry with an anti-active antibody) is spatially coincident with the onset of IEG induction [c-fos, zif 268, and map kinase phosphatase-1 (MKP-1) detected by in situ hybridization] in the striatum, bilaterally. Both Elk-1 and CREB transcription factors (targeting SRE and CRE DNA regulatory elements, respectively) were hyperphosphorylated in register with ERK activation and IEG mRNA induction. However, their hyperphosphorylation occurred in different subcellular compartments: the cytoplasm and the nucleus for Elk-1 and the nucleus for CREB. The role of the ERK signaling cascade in gene regulation was confirmed after intrastriatal and unilateral injection of the specific ERK inhibitor PD 98059, which completely abolished c-fos, zif 268, and MKP-1 mRNA induction in the injected side. Of interest, both Elk-1 and CREB hyperphosphorylation also was impaired after PD 98059 injection. Thus two different ERK modules, one depending on the cytoplasmic activation of Elk-1 and the other one depending on the nuclear activation of CREB, control IEG transcriptional regulation in our model. Our findings provide significant insights into intracellular mechanisms underlying synaptic plasticity in the striatum.

Alcohol Relapse Induced by Discrete Cues Activates Components of AP-1 Transcription Factor and ERK Pathway in the Rat Basolateral and Central Amygdala

“…The rats were killed 30 (for P-c-Jun and P-ERK1/2) or 90 min (for c-Fos) after the start of the final session or 30 or 90 min after the handling episode in the case of the naive animals. Alcohol relapse activates amygdala K Radwanska et al and c-Jun phosphorylation, respectively (Sgambato et al, 1998). Given the above, we decided to assess the activation pattern of phosphorylated, ie activated, ERK1/2 and JNK1/2.…”

“…It has been shown that c-Fos expression is induced in the amygdala after reexposure to drug-related stimuli (Brown et al, 1992;Neisewander et al, 2000;Ciccocioppo et al, 2001). The upstream regulators of this event are mostly unknown although possible candidates are extracellular signal-regulated kinases (ERK) which have been found to control c-fos expression in many experimental paradigms (Sgambato et al, 1998;Radwanska et al, 2005). Furthermore, ERKs have been shown to be activated in the central amygdala (CeA) after cue-induced relapse to cocaine seeking and inhibition of ERKs in the CeA decreased cocaine seeking after drug withdrawal (Lu et al, 2005).…”

“…For this aim, we analyzed the activation pattern of c-Jun, as well as ERKs (ERK1 and 2) and c-Jun Nterminal kinases (JNK1 and 2), ie protein kinases known to regulate the expression of c-fos and phosphorylation of c-Jun, respectively (Gupta et al, 1996;Sgambato et al, 1998).…”

MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide

“…6). Furthermore, the transcription of Cu/ZnSOD is regulated by the transcription factor ELK-1 [35] and the promoter for MnSOD expression contain binding sites for Sp1, AP-1, and CREB [47,181], all of which have been linked to regulation by ERK1/2 [18,182] (Fig. 6).…”

“…The expression of some enzymes implicated in antioxidant defences such as the enzymes for glutathione synthesis [235] and heme oxygenase [37] exhibit ERK1/2 dependency in the regulation of their expression. Furthermore, the transcription of Cu/ZnSOD is regulated by the transcription factor ELK-1 [35] and the promoter for MnSOD expression contain binding sites for Sp1, AP-1, and CREB [35,47], all of which have been linked to regulation by ERK1/2 [34,182].…”