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Importantly, the effects of TGF-b1 and b-neuregu-lin-1 persist in the presence of protein synthesis inhibitors (Subramony et al., 1996). These studies indicate that new protein synthesis is not required for the developmental upregulation of KCa channel expression mediated by TGF-b1 and b-neuregulin-1 in chick ciliary neurons. Interestingly, the effects of extrinsic factors on developmental regulation of current in chick lumbar motor neurons do require new protein synthesis (Martin-Caraballo and Dryer, 2002a, 2002b).

More recent studies suggest that the effects of TGF-^1 on ciliary ganglion neurons lead to surface membrane insertion of presynthesized KCa channels (Lhuillier and Dryer, 2002). This finding is especially significant because large intracellular pools of several different types of VGICs have been observed. Thus, for several different types of ion channels, post-translational control of surface membrane insertion would be an effective and possible way to regulate functional expression of current (for review, see Misonou and Trimmer, 2004).

Conversely, post-translational regulation of ion channels in the surface membrane could result in their removal. For example, activation of sodium channels and sodium influx leads to removal of these channels from the surface membrane (Dargent and Couraud, 1990; Dargent et al., 1994). This type of regulation might function after circuit formation as a homeostatic mechanism to keep channel densities and electrical activity in an optimal range (for review, see Turrigiano and Nelson, 2004).

1.13.8.3.2 Glycosylation In the adult nervous system, glycosylation promotes proper protein folding, function, stability, intracellular sorting, and membrane targeting (Bar-Sagi and Prives, 1983; West, 1986; Marban et al., 1998; Tyrrell et al., 2001). For some plasma membrane sodium channels, removal of glycosylation leads to changes in the voltage dependence of gating (Recio-Pinto et al., 1990; Bennett et al., 1997; Zhang et al., 2003). Notably, depolarizing shifts in the steady-state activation and inactivation curves are produced (Recio-Pinto etal.,

1990; Bennett et al., 1997; Zhang et al., 2003). Of particular interest is the finding that the glycosylation levels of voltage-gated sodium channels are develop-mentally regulated and linked to modulation of voltage-dependent properties (Tyrrell et al., 2001). Further, glycosylation of sodium channels has been linked to developmentally regulated changes in single-channel conductance and steady-state activation (Castillo et al., 1997, 2003). In comparison to sodium channels, much less is known about developmental regulation of glycosylation for other VGICs.

1.13.8.3.3 Phosphorylation Protein phosphoryla-tion and dephosphorylation underlie modulation of the activity of ion channels and modulate neuronal excitability (for review, see Levitan, 1999). VGIC a-subunits are common substrates for phosphorylation mediated by the major protein kinases, including cyclic adenosine monophosphate-depen-dent kinase (PKA), protein kinase C (PKC), calcium calmodulin kinase II (CAM kinase II), and tyrosine kinase. Moreover, electrophysiological studies indicate that key properties of VGIC can be modified by phosphorylation, at least in the mature nervous system (Brum et al., 1983; Flockerzi et al., 1983; Emerick and Agnew, 1989; Perozo and Bezanilla, 1990, 1991; Armstrong et al., 1991; Hoger et al., 1991; Murphy and Catterall, 1992; Covarrubias et al., 1994; Cohen, 1996; Cohen et al., 1996; Roeper et al., 1997; Beck et al., 1998). Comparatively little is known about the role of phos-phorylation in developmental regulation of ion channel function. However, expression of kinases, such as CAM kinase II, is developmentally regulated (Hanson and Schulman, 1992; Menegon et al., 2002). Further, this kinase participates in developmental regulation of synapse formation (Zou and Cline, 1996; Wu and Cline, 1998). These findings motivate further study of the potential role of phos-phorylation in the developmental regulation of VGIC function.

1.13.8.3.4 Auxiliary subunits Auxiliary (also known as accessory) subunits form complexes with the pore-forming subunits of VGICs. Pore-forming subunits are typically designated as a whereas auxiliary ones are referred to by another Greek letter, such as ß. Auxiliary subunits influence the kinetic properties and the voltage dependence of VGIC activation and inactivation (Isom et al., 1992; Patton et al., 1994; Rettig et al., 1994; Morales et al., 1995; Heinemann et al., 1996) without major effects on ion conductance (for review, see Trimmer, 1998; Hanlon and Wallace, 2002). Further, auxiliary subunits have effects on the assembly and expression of VGICs (Patton et al., 1994; Isom et al., 1995a, 1995b; Qu et al., 1995; Shi et al., 1996; for review, see Isom et al., 1994; Striessnig, 1999; Goldin, 2001). Because many of these properties are developmentally regulated, the role of auxiliary subunits during differentiation of excitability is of interest.

Spatial and developmental regulation of VGIC auxiliary subunit expression has been observed in several types of excitable tissue, including brain, muscle, and heart (Butler et al., 1998; Downen et al., 1999; Lazaroff et al., 1999; Franco et al., 2001; Falk et al., 2003; Grande et al., 2003). Very little evidence exists linking auxiliary subunits to developmental regulation of excitability (but see Falk et al., 2003).

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