Abstract:We investigated mitogen-activated protein kinase (MAPK) modulation of dendritic, A-type K+ channels in CA1 pyramidal neurons in the hippocampus. Activation of cAMP-dependent protein kinase A (PKA) and protein kinase C (PKC) leads to an increase in the amplitude of backpropagating action potentials in distal dendrites through downregulation of transient K+ channels in CA1 pyramidal neurons in the hippocampus. We show here that both of these signaling pathways converge on extracellular-regulated kinases (ERK)-sp… Show more
“…An emerging model suggests that activated ERK1/2 participate in several pathways that work together to induce synaptic plasticity (English and Sweatt, 1997;Lamprecht and LeDoux, 2004). Thus, ERK1/2 modulate back-propagating action potentials by phosphorylating dendritic A-type K + channels (Kv4.2 subunits) (Watanabe et al, 2002;Yuan et al, 2002;Morozov et al, 2003), and is one of several signaling cascades shown to initiate local protein synthesis after synaptic activation through phosphorylation of translation factors (eIF4E) and ribosomal protein S6 (Kelleher et al, 2004a(Kelleher et al, , 2004b). …”
Background-Formation of long-term memories is critically dependent on extracellular-regulated kinase (ERK) signaling. Activation of the ERK pathway by the sequential recruitment of mitogenactivated protein kinases is well understood. In contrast, the proteins that inactivate this pathway are not as well characterized.
“…An emerging model suggests that activated ERK1/2 participate in several pathways that work together to induce synaptic plasticity (English and Sweatt, 1997;Lamprecht and LeDoux, 2004). Thus, ERK1/2 modulate back-propagating action potentials by phosphorylating dendritic A-type K + channels (Kv4.2 subunits) (Watanabe et al, 2002;Yuan et al, 2002;Morozov et al, 2003), and is one of several signaling cascades shown to initiate local protein synthesis after synaptic activation through phosphorylation of translation factors (eIF4E) and ribosomal protein S6 (Kelleher et al, 2004a(Kelleher et al, , 2004b). …”
Background-Formation of long-term memories is critically dependent on extracellular-regulated kinase (ERK) signaling. Activation of the ERK pathway by the sequential recruitment of mitogenactivated protein kinases is well understood. In contrast, the proteins that inactivate this pathway are not as well characterized.
“…MEK directly phosphorylates and activates ERK (Crews and Erikson, 1992), whereas PKA and PKC regulate ERK activity by indirect, MEK-dependent (Yuan et al, 2002) or MEKindependent mechanisms (Grammer and Blenis, 1997;Kinkl et al, 2001). Similarly, extensive intracellular crosstalk between hippocampal PKA, PKC, and MEK converging at ERK was shown in hippocampal slices (Roberson et al, 1999) and in vivo (Ahi et al, 2004).…”
Human anxiety is frequently accompanied by depression, and when they co-occur both conditions exhibit greater severity and resistance to treatment. Little is known, however, about the molecular processes linking these emotional and mood disorders. Based on previously reported phosphorylation patterns of extracellular signal-regulated kinase (ERK) in the brain, we hypothesized that ERK's upstream activators intertwine fear and mood regulation through their hippocampal actions. We tested this hypothesis by studying the upstream regulation of ERK signaling in behavioral models of fear and depression. Wild-type and ERK1-deficient mice were used to study the dorsohippocampal actions of the putative ERK activators: mitogen-activated and extracellular signal-regulated kinase (MEK), protein kinase C (PKC), and cAMP-dependent protein kinase (PKA). Mice lacking ERK1 exhibited enhanced fear extinction and reduced depression caused by overactivation of ERK2. Both behaviors were reversed by inhibition of MEK, however the extinction phenotype depended on hippocampal, whereas the depression phenotype predominantly involved extrahippocampal MEK. Unexpectedly, inhibition of PKC accelerated extinction and decreased depression by ERK-independent mechanisms, whereas inhibition of PKA did not produce detectable molecular or behavioral effects in the employed paradigm. These results indicate that, contrary to fear conditioning but similar to mood stabilization, extinction of fear required upregulation of MEK/ERK and downregulation of ERK-independent PKC signaling. The dissociation of these pathways may thus represent a common mechanism for fear and mood regulation, and a potential therapeutic option for comorbid anxiety and depression.
“…Neuromodulators strongly regulate these channels through phosphorylation, association with auxiliary subunits, and expression-level control. A-type potassium channels modulate the action potential broadening, b-AP (backpropagation of action potentials), spike generation, and integration of synaptic inputs (Ramakers and Storm 2002;Watanabe et al 2002;Yuan et al 2002;Birnbaum et al 2004;Lauver et al 2006;Hammond et al 2008;Kim and Hoffman 2008). Among the A-type potassium channels, the Kv4 channels adjust dendritic function by limiting spike-timing-dependent plasticity.…”
Kv4 channels regulate the backpropagation of action potentials (b-AP) and have been implicated in the modulation of longterm potentiation (LTP). Here we showed that blockade of Kv4 channels by the scorpion toxin AmmTX3 impaired reference memory in a radial maze task. In vivo, AmmTX3 intracerebroventricular (i.c.v.) infusion increased and stabilized the EPSP-spike (E-S) component of LTP in the dentate gyrus (DG), with no effect on basal transmission or short-term plasticity. This increase in E-S potentiation duration could result from the combination of an increase in excitability of DG granular cells with a reduction of GABAergic inhibition, leading to a strong reduction of input specificity. Radioactive in situ hybridization (ISH) was used to evaluate the amounts of Kv4.2 and Kv4.3 mRNA in brain structures at different stages of a spatial learning task in naive, pseudoconditioned, and conditioned rats. Significant differences in Kv4.2 and Kv4.3 mRNA levels were observed between conditioned and pseudoconditioned rats. Kv4.2 and Kv4.3 mRNA levels were transiently up-regulated in the striatum, nucleus accumbens, retrosplenial, and cingulate cortices during early stages of learning, suggesting an involvement in the switch from egocentric to allocentric strategies. Spatial learning performance was positively correlated with the levels of Kv4.2 and Kv4.3 mRNAs in several of these brain structures. Altogether our findings suggest that Kv4 channels could increase the signal-to-noise ratio during information acquisition, thereby allowing a better encoding of the memory trace.
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