The Mitogen-Activated Protein Kinase Cascade Couples PKA and PKC to cAMP Response Element Binding Protein Phosphorylation in Area CA1 of Hippocampus

Abstract

Activation of the mitogen-activated protein kinase (MAPK) cascade recently was discovered to play an important role in synaptic plasticity in area CA1 of rat hippocampus. However, the upstream mechanisms regulating MAPK activity and the downstream effectors of MAPK in the hippocampus are uncharacterized. In the present studies we observed that hippocampal MAPK activation is regulated by both the PKA and PKC systems; moreover, we found that a wide variety of neuromodulatory neurotransmitter receptors (metabotropic glutamate receptors, muscarinic acetylcholine receptors, dopamine receptors, and beta-adrenergic receptors) couple to MAPK activation via these two cascades. In additional studies we observed that PKC is a powerful regulator of CREB phosphorylation in area CA1. MAPK plays a critical role in transcriptional regulation by PKC, because MAPK activation is a necessary component for increased CREB phosphorylation in response to the activation of this kinase. Surprisingly, we also observed that MAPK activation is necessary for PKA coupling to CREB phosphorylation in area CA1. Overall, these studies indicate an unexpected richness of diversity in the regulation of MAPK in the hippocampus and suggest the possibility of a broad role for the MAPK cascade in regulating gene expression in long-term forms of hippocampal synaptic plasticity.

Xenon Preconditioning Reduces Brain Damage from Neonatal Asphyxia in Rats

“…Upstream of pCREB, N 2 O and xenon exhibit divergent effects on PKC signalling; preconditioning with xenon upregulates PKC activity (Weber et al, 2005), while N 2 O has been shown to inhibit PKC activity (Fukura et al, 2000). PKC is able to phosphorylate CREB (Roberson et al, 1999); together with its transcriptional coactivator, CBP, pCREB upregulates the expression of a number of genes, including Bcl-2 and BDNF (Wilson et al, 1996;Tao et al, 1998) and their corresponding proteins. In our study, we did show upregulation of pCREB and Bcl-2 as well as BDNF and this pathway may contribute to the mechanism for the preconditioning effect exerted by xenon (Figure 7).…”

“…(Weber et al, 2005). Consequently, cAMP-response element-binding protein (CREB) is transformed into the phospho-CREB (pCREB) form (Roberson et al, 1999). The CREB and CREB-binding protein (CBP) interaction can then induce transcription of a battery of CREB-dependent survival genes.…”

Modulation of Neuronal Excitability by Serotonin-NMDA Interactions in Prefrontal Cortex

“…ERK can be regulated by the PKA or PKC cascade (Roberson et al, 1999) downstream of 5-HT 1A or 5-HT 2A/C receptors. However, application of the low concentration of 5-HT 1A or 5-HT 2A/C agonist (e.g.…”

“…As shown in Figure 4A and 4B, the reducing effect of 8-OH-DPAT (with NMDA present) on spikes was prevented in cells dialyzed with the PKA inhibitor PKI 6-22 (20 μM, -6.9 ± 3.0%, n = 5, Figure 4E), while it was not affected by the PKC inhibitor calphostin (1 μM, Figure 4C, 30.6 ± 3.5%, n = 4, Figure 4E), suggesting the specific involvement of PKA. Since inhibition of PKA could result in the inhibition of ERK via the Rap1/B-Raf/MEK cascade (Vossler et al, 1997;Roberson et al, 1999), we also examined the involvement of ERK in the 5-HT 1A regulation of AP firing. As shown in Figure 4D, injecting cells with the ERK kinase inhibitor U0126 (20 μM) prevented 8-OH-DPAT from reducing the firing rate (-5.0 ± 2.3%, n = 12, Figure 4E).…”

“…As shown in Figure 5A-D, α-Me-5HT (with NMDA present) lost its capability to increase the firing rate in neurons loaded with the PLC inhibitor U73122 (5 μM, 8.8 ± 2.0%, n = 6, Figure 5F) or the PKC inhibitor calphostin (1 μM, 7.9 ± 2.4%, n = 5, Figure 5F), but not the PKA inhibitor PKI 6-22 (20 μM, 29.15 ± 3.3%, n = 4, Figure 5F), suggesting the specific involvement of PKC. Since activation of PKC could result in the activation of ERK via the Ras/Raf-1/MEK cascade (Roberson et al, 1999), we also examined the involvement of ERK in the 5-HT 2A/C regulation of AP firing. As shown in Figure 5E, dialysis with the ERK kinase inhibitor U0126 (20 μM) prevented α-Me-5HT from increasing the firing rate (8.4 ± 3.2%, n = 8, Figure 5F).…”