In the nervous system, developmental regulation of ion channels is not unique to neurons. Glial cells also display developmentally regulated properties of excitability (Sontheimer et al., 1992; Kressin et al., 1995; Bordey and Sontheimer, 1997; Maric et al., 1998; Bringmann et al., 2000; Pannicke et al., 2002; for review, see Waxman et al., 1993). The distribution of specific sodium and potassium channel isoforms in myelinated axons provides one of the most interesting examples of developmental regulation of ion channels. Recent studies have revealed that interactions between axons and glia during development play key roles in sculpting the differential localization of VGICs in the axonal membrane.
Glial cells wrap around axons and form several layers of membrane known as myelin (for review, see Sherman and Brophy, 2005). The identities of the glial cells that form myelin differ in the peripheral versus central nervous systems. In the central nervous system, oligodendrocytes form myelin. Schwann cells are the relevant glia for the peripheral nervous system.
Myelination of axons in both the peripheral and central nervous systems underlies the amazing ability of axons to propagate APs rapidly (for review, see Sherman and Brophy, 2005). Myelin provides insulation to the axon and current flow is restricted to nonmyelinated areas, known as nodes ofRanvier. Consequently, APs need not be conducted down the entire length of the axon but only to successive nodes of Ranvier, thereby accelerating AP conduction velocities. Further, the metabolic demands of transmitting APs over long distances are diminished because impulses are only generated at nodes and not throughout the entire length of the axon.
Morphological studies indicate that myelin is present in jawed vertebrates but not lamprey or hagfish (Bullock et al., 1984). In addition, a few copepod crustacean species that display rapid escape behaviors necessary for life in predator-rich ocean waters also have myelin (Davis et al., 1999). The copepods that display rapid behaviors and myelin-like sheaths are thought to have evolved later than other members of their species. Thus, myelin represents a relatively recent evolutionary adaptation that results in rapid behavioral responses.
220.127.116.11 Distribution of Ion Channels during Developmental Myelination
Toxin labeling studies indicated that axons have an overall low density of sodium channels, even though they can propagate APs (Waxman et al., 1989). These studies raised the possibility that, in addition to myelin, the distributions of VGICs may be optimized for generation of APs at nodes of Ranvier. More recent immunocytochemical studies have demonstrated that sodium channels are maintained at high densities at nodes of Ranvier (for review, see Rasband and Trimmer, 2001; Figure 6). In contrast, specific potassium channel isotypes are maintained at high densities in nearby, non-nodal regions known as the juxtaparanodes. Moreover, the specific locations of the different ion channel types are specified during developmental myelination and require interactions between the axon and glia (Wu and Barish, 1994; Demerens et al., 1996; Stevens et al., 1998; Stevens and Fields, 2000).
In both the peripheral and central nervous systems, one sodium channel isoform, Nav1.2, appears early in unmyelinated zones (Westenbroek et al., 1992; Gong et al., 1999; Boiko et al., 2001; for review, see Rasband and Trimmer, 2001). As nodes form, another isoform, Nav1.6, becomes the dominant sodium channel type (Caldwell et al., 2000; Boiko et al., 2001; for review, see Rasband and Trimmer, 2001).
Potassium channels also display stereotypic distributions in myelinated axons. Electrophysiological studies demonstrated that potassium current densities were not constant across the length of myelinated axons, suggesting nonhomogeneous, optimized distributions of potassium channels (Chiu and Ritchie, 1980; Chiu and Wilson, 1989; Roper and Schwarz, 1989). Immunocytochemical results have directly demonstrated the locations of specific potassium channel subtypes in myelinated axons. In myelinated axons, potassium channel
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