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¹ Osaka Bioscience Institute, 6-2-4 Furuedai, Suita, Osaka 565-0874, Japan

In many developing neuronal cell types, the resting membrane potential is relatively depolarized, then gradually hyperpolarizes during the early postnatal period. The regulatory roles of membrane potential changes in neuronal development and maturation have been extensively studied in developing cerebellar granule cells, using primary culture under depolarizing and non-depolarizing conditions in combination with in vivo analysis. Depolarization enhances calcium entry via voltage-sensitive Ca²⁺ channels (VSCCs) and activates Ca²⁺–calmodulin-dependent protein kinase (CaMK) and calcineurin phophatase (CaN). The activation of CaN induces many genes encoding extracellular and intracellular signalling molecules implicated in granule cell development. The inactivation of CaN in turn up-regulates many other genes characteristic of mature granule cells, including NR2C NMDA receptor and GABA_A1 and 6 receptors. The induction of NR2C also requires CaMK-up-regulated brain-derived neurotrophic factor (BDNF), indicating a convergence of signalling mechanism of the CaMK and CaN cascades. The inactivation of CaN maintains the phosphorylated and sumoylated form of a transcriptional myocyte enhances factor 2A (MEF2A) regulator. This form of MEF2A acts as a transcriptional repressor and is essential for the dendritic morphogenesis of differentiated granule cells. Collectively, the membrane potential change and the resulting Ca²⁺ signalling play a pivotal role in development and maturation of neuronal cells.

(Received 11 May 2006; accepted after revision 20 June 2006; first published online 22 June 2006)
Corresponding author S. Nakanishi: Osaka Bioscience Institute, 6-2-4 Furuedai, Suita, Osaka 565-0874, Japan. Email: snakanis{at}obi.or.jp

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