MAP Kinase Signaling in Learning and Memory

Introduction of MAP Kinase Signaling Pathway

MAP kinase (MAPK), mitogen-activated protein kinase, is a serine/ threonine specific kinase that is activated by a wide range of stimuli including mitogens, proinflammatory cytokines, growth factors, osmotic stress, heat shock, and so on. MAPK functions in intracellular signaling cascades and is involved in regulating a variety of cellular activities such as proliferation, differentiation, gene expression, mitosis, cell survival, apoptosis, synaptic plasticity, and long-term memory. The MAPK signaling cascade is initiated by the binding of specific extracellular cues, such as mitogen, to the receptor on the cell surface, such as Ras. Upon the extracellular ligands binding to the receptors, MAPK kinase (MAP3K) is activated. Subsequently, MAP3K directly phosphorylates and activates the MAPK kinase (MAP2K) which then activates the MAPK by activating the dual phosphorylation of the conserved tripeptide TxY motif in the segment. Once activated, the MAPK phosphorylates a variety of substrates in the cytoplasm and nucleus, resulting in alterations in protein function and gene expression to perform appropriate biological responses.

In mammals, the MAPK can be grouped into three main families, ERKs (extracellular-signal-regulated kinases), JNKs (Jun amino-terminal kinases), and p38/SAPKs (stress-activated protein kinases). Among them, MAPK/ERK signaling pathway is one of the most concerned signaling pathways, which is involved in cell growth, development, proliferation, differentiation and malignant transformation of cells, and other physiological and pathological processes. In recent years, more and more studies have confirmed that MAPK/ERK signaling pathways are associated with the formation of long-term potentiation (LTP) as well as learning and memory.

Fig.1 The modules and various components of the MAPK signaling pathways. (Haddad, 2007)

Role of MAPK/ERK in Learning and Memory

• Cognitive Function

Silva et al. used genetic engineering technology to study the association of I type neurofibroblastoma (NF1) and mental retardation and found a decrease of learning function was closely related to the absence of hippocampal RAS/ERK signaling pathways. Neurofibromin encoded by NF1 gene acts as the GTP synthase activated protein (GAP) of RAS and participates in the activation of ERK pathway. Mutations in the NF1 gene destroy the activity of GAP, resulting in RAS overactivity of the hippocampal region, which in turn causes over excitation of the RAS/ERK pathway, reducing the learning and memory function and leading to the development of mental disorders.

• Synaptic Plasticity

At present, it is widely believed that LTP is the possible mechanism of learning and memory at the cellular level. The induction of LTP usually requires activation of NMDA receptors, which is mainly regulated by type A potassium ion channels encoded by members of the Kv4 family. Yuan et al. found that phosphorylation of Kv4.2α subunit could be induced by activation of ERK after activation of β-adrenergic receptor in hippocampal CA1 region of rats and cascading activation of PKA and PKC. This process could be blocked by ERK inhibitors, UO126 or PD98059. Phosphorylation of Kv4.2 induces down-regulation of type A potassium ion current and amplification of action potential (AP), enhancing the excitability of dendritic cell membrane, furthermore affecting information storage and memory consolidation in the brain.

In addition, there has a lot of evidence to describe the association of ERK pathway and learning and memory. For example, Goldin et al. found ERK participates in the regulation of formation and changes of dendritic spines in hippocampal neurons, which may be related to the long-term storage of information in the central nervous system. Kelleher et al. found ERK was directly involved in the regulation of dendritic protein synthesis which is required for LTP formation and memory function.

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Reference

1. Haddad, J.J. The Emphatic Role of Mitogen-Activated Protein Kinases (MAPKs) in the Cellular Mechanisms Mediating Alzheimer's Disease. EXCLI Journal. 2007. 6:36-67.