Mechanisms of Developmental Regulation

Even though developmental changes in potassium currents typically drive maturation of the AP, most VGICs show developmental regulation. Analyses of mRNA and protein indicate that regulation of ion channel expression occurs across both temporal and spatial domains (Table 1). Electrophysiological analyses further indicate that the properties of voltage-gated currents expressed by a given cell are not constant over time but change during differentiation and in response to activity (Table 2).

Developmental regulation of channel function could occur at transcriptional, post-transcriptional, translational, and post-translational levels. These levels of control are not mutually exclusive and several could be operating simultaneously (Giraud et al., 1998; Blaine et al., 2004).

In some cases, developmental regulation of ion currents occurs in the absence of interactions with other cells or factors (Henderson and Spitzer, 1986). Additionally, cell-cell interactions, often apparent at the onset of synaptogenesis, play important roles (Okado and Takahashi, 1990a, 1990b; Okamura et al., 1994; Subramony et al., 1996; Bahls et al., 1998; Nick and Ribera, 2000; Martin-Caraballo and Dryer, 2002a). Growth factors and neurotro-phins often mediate the effects of activity or cell-cell interactions (Subramony et al., 1996; Rothe et al., 1999; Martin-Caraballo and Dryer, 2002a; for review, see Dryer et al., 2003).

Further, extrinsic cues affect functional expression of VGICs differently depending upon the neuron type. For example, growth factors regulate expression of currents post-translationally in ciliary ganglion neurons but their effects require new protein synthesis in lumbar motor neurons (Subramony et al., 1996; Martin-Caraballo and Dryer, 2002a). Thus, both intrinsic and extrinsic cues operate to regulate ion currents during development (for review, see Dryer, 1998; Ribera, 1998).

In Table 1, we review the molecular bases of developmental regulation of ion channel expression and function in the developing nervous system.

1.13.8.1 Transcriptional Regulation

Numerous stimuli, such as injury, electrical activity, growth factors, and development, modulate VGIC gene transcription (Beckh et al., 1989; Ribera and Nguyen, 1993; Toledo-Aral et al., 1995; Burger and Ribera, 1996; Gurantz et al., 1996; Villeneuve et al., 2000; Vega et al., 2003; for review, see Levitan and Takimoto, 1998; Sashihara et al., 1998; Black and Grabowski, 2003). Recent

Table 1 Developmentally and spatially specific expression of ion channels

VGIC type

Molecular identity

Regulation

Neuron type

References

Sodium

Nav1.3

Expression of Nav1.3 was linked to

Murine preplate and

Albrieux et al.

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