As described in several preceding chapters, recent advances have given us a much more detailed understanding of the signal transduction mechanisms subserving learning in the intact animal and one fact that has become clear is that protein kinases play a critical role in these processes. Most recently, the Mitogen-Activated Protein Kinase (MAPK) superfamily of signaling cascades has achieved some notoreity as a player in learning and memory. The MAPK superfamily includes three subfamilies: the ERK (extracellular signal-regulated kinase) family, the p38 MAPK family, and the jun kinase (JNK) family. Each subcategory of the superfamily has a common motif, a characteristic core cascade of three kinases. The first kinase in each cascade is a so-called MAP kinase kinase kinase (MAPKKK, e.g., Raf-1 and B-Raf in the ERK cascade, see Fig. 1) which activates the second, a MAP kinase kinase (MAPKK, e.g., MEK in
From Messengers to Molecules: Memories Are Made of These, edited by Gernot Riedel and Bettina Platt. ©2004 Eurekah.com and Kluwer Academic / Plenum Publishers.
Figure 1. ERK activation and inhibition. Schematic of the ERK MAPK cascade. The classic MAP kinase cascade consists ofat least 3 protein kinases beginning with the serine/ threonine kinases, Raf-1 and B-Raf, which phosphorylate the MAP kinase kinase MEK. MEK, in turn, is a dedicated, dual-specificity kinase that phosphorylates and thereby activates both the ERK1 and ERK2 isoforms of MAP kinase. These isoforms are the only known effectors of MEK, and MEK is the only known direct activator of the ERK MAPKs. Also depicted are the MEK inhibitors U0126 and SL327. SL327 is capable of crossing the blood-brain barrier and is therefore amenable to behavior studies.
the ERK cascade), by serine/threonine phosphorylation. MAPKKs are dual specificity kinases which in turn activate a MAP kinase (e.g., ERK1, ERK2) by phosphorylating threonine and tyrosine moieties (reviewed in ref. 44).
In addition to serving as a target for growth factor/tyrosine kinases in general, ERK serves as an important point of convergence for the PKC and PKA pathways, both of which have been shown to play critical roles in synaptic plasticity and learning (for review see refs. 1, 2, 19, 102 and also Nogues et al and Vianna and Izquierdo in this book). For example, PKC regulates ERK activity through an interaction with either Ras or Raf-1 leading to activation of MEK and consequently the ERKs. Interestingly, a family of phorbol ester-binding Ras/Rap guanine nucleotide exchange factors (GEFs) was recently discovered that allows the second messenger diacylglycerol (DAG) to achieve ERK activation independent of PKC activation.35
In another example of cross talk between two kinase systems, PKA can also couple, both negatively and positively to the ERK cascade. In some cell types, PKA can attenuate ERK activity through inhibition of the Ras/Raf-1 pathway. In an important breakthrough, however, Stork and coworkers discovered that cAMP could also be positively coupled to ERK activation in neurons by signaling through the Ras homologue, Rap1 to activate the B-Raf pathway.100 Like Raf-1, B-Raf is a serine/threonine kinase that can activate MEK and therefore ERK. In addition, a cAMP-responsive GEF was recently discovered that also leads to ERK activation, independent of PKA.58
Simplifying what is a rather complex network of upstream activators is the fact that ERK activity is exclusively regulated by MEK. Dual phosphorylation by MEK has been shown to be both necessary and sufficient for ERK activation. This is a convenient feature of the ERK system as it allows for monitoring of ERK activation using commercially available phospho-specific antibodies recognizing phosphorylation at Thr202 and Tyr204 (see ref. 81 for example). In addition to easing detection of ERK activation, this attribute also has been capitalized upon to create three pharmacologic tools used to investigate the ERK cascade experimentally: the MEK inhibitors PD098059,5 U0126,34 and SL327.8 By inhibiting MEK, these agents effectively block ERK activation and lend themselves well to studies in vitro. Of these inhibitors, SL327 is particularly important for behavioral studies due to its ability to cross the blood-brain barrier and achieve effective concentrations in the CNS when administered systemically.8
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