**1. Introduction**

Conventional mitogen-activated protein kinases (MAPKs) involve extracellular signal-regulated kinases (ERKs) 1, 2, and 5, c-Jun N-terminal kinase and p38 MAPKs, and atypical MAPKs include ERK3, 4, and 7 and nemo-like kinase [1]. In response to growth factors or neurotrophic factors, ERKs are strongly activated and regulate diverse physiological responses, such as proliferation, differentiation, and gene expression. The signal transduction leading to ERK1/2 activation and the involvement of ERK1/2 in cellular responses are the best studied among the MAPK family members.

ERK5 shares homology in the amino acid sequence in the kinase-domain with ERK1/2, and possesses a unique long C-terminal domain [2,3]. In the past 10 years, specific inhibitors of ERK5 signaling, such as BIX02189 [4,5] and XMD8-92 [6], have been developed. Using these pharmacological inhibitors, the role of ERK5 in tumor genesis and metastatic progression has been especially well understood [7,8]. We have shown that the levels of ERK5 and tyrosine hydroxylase, a rate-limiting enzyme for catecholamine biosynthesis, are co-related in normal human adrenal medulla, but this correlation is disrupted in pheochromocytomas [9]. However, signaling pathways for ERK5 activation

and physiological roles of ERK5 in neuronal development are relatively unclear. For example, involvements of small G-proteins in ERK5 activation are vague [10], whereas it has been established that ERK1/2 is activated through Ras and Rap1 [11,12]. Some limited studies suggest that ERK5 is necessary and sufficient for neuronal differentiation of progenitor cells [13], and is essential for adult hippocampal neurogenesis [14,15]. ERK5 promotes neuronal survival in sympathetic or sensory neurons [16,17]. We have shown that ERK5 is essential for neurite/axon outgrowth and catecholamine biosynthesis in PC12 cells and sympathetic neurons [5,9]. Thus, ERK5 plays important roles in neuronal survival, as well as morphological and functional differentiation. However, although it is well known that ERK1/2 regulates membrane excitability (i.e., neuronal activity) [18–21], ERK5 regulation of membrane excitability has been poorly understood. Therefore, in the present study, we attempted to clarify the effect of ERK5 signaling on ion channel activity, which is important for regulating membrane excitability.
