Functional Role of Nav12

The widespread expression of Nav1.2, extending for tens of microns along demyelinated axons in EAE and in MS, is similar to the diffuse expression of Nav1.2 immunostaining that has been reported along axons during early development

Figure 6 The Na/Ca exchanger and Nav1.6 are co-expressed in P-APP-positive axons in MS. Histogram (left) showing the proportions of P-APP-positive axons and P-APP-negative axons that co-express the Na/Ca exchanger and Nav1.6 or the Na/Ca exchanger and Nav1.2, over extensive regions. The proportion of axons that co-express Nav1.6 and the Na/Ca exchanger is significantly higher in P-APP-positive axons than in P-APP-neg-ative axons. *P < 0.005. Digital images (right) demonstrate representative axons in MS spinal cord white matter immunostained for P-APP (blue; E, F), Nav1.6 (red; A) or Nav1.2 (red; B), and Na/Ca exchanger (green; C, D). Panels G and H show merged images (white). Panels A, C, E and G show co-expression of Nav1.6 and Na/Ca exchanger within axons displaying P-APP, a marker of axonal injury. In contrast, panels B, D, F, and H demonstrate the Na/Ca exchanger but an absence of Nav1.2 within P-APP-positive axons, and co-expression the Na/Ca exchanger and Na 1.2 within P-APP-negative axons. (From Craner at al., 2004b.)

Figure 6 The Na/Ca exchanger and Nav1.6 are co-expressed in P-APP-positive axons in MS. Histogram (left) showing the proportions of P-APP-positive axons and P-APP-negative axons that co-express the Na/Ca exchanger and Nav1.6 or the Na/Ca exchanger and Nav1.2, over extensive regions. The proportion of axons that co-express Nav1.6 and the Na/Ca exchanger is significantly higher in P-APP-positive axons than in P-APP-neg-ative axons. *P < 0.005. Digital images (right) demonstrate representative axons in MS spinal cord white matter immunostained for P-APP (blue; E, F), Nav1.6 (red; A) or Nav1.2 (red; B), and Na/Ca exchanger (green; C, D). Panels G and H show merged images (white). Panels A, C, E and G show co-expression of Nav1.6 and Na/Ca exchanger within axons displaying P-APP, a marker of axonal injury. In contrast, panels B, D, F, and H demonstrate the Na/Ca exchanger but an absence of Nav1.2 within P-APP-positive axons, and co-expression the Na/Ca exchanger and Na 1.2 within P-APP-negative axons. (From Craner at al., 2004b.)

before myelination and in genetic dysmyelination (Boiko et al., 2001). Diffusely distributed Nav1.2 channels are also present along nonmyelinated axons within the CNS (Westenbroek et al., 1989; Gong et al., 1999; Whitaker et al., 2000) where they appear to support action potential conduction.

Nav1.2 and Nav1.6 sodium channels both produce rapidly activating and inactivating currents that can support action potential electrogenesis, but the two channel subtypes exhibit some different functional properties. The rapid repriming kinetics of Nav1.6 channels (Herzog et al., 2003) can support sustained high rates of firing while Nav1.2 channels have slower repriming kinetics, support low-frequency firing, and are more likely to generate activity in response to sustained or slow depolarizations (Zhou and Goldin, 2002; Herzog et al., 2003). As discussed later, Nav1.2 channels produce significantly less persistent current than Nav1.6 channels (Smith et al., 1998; Goldin, 2001), a factor that may permit Nav1.2 to be expressed along pre-myelinated and demyelinated axons without causing axonal degeneration. The conduction of action potentials, although with slowed conduction velocities, along CNS fibers before maturation of myelin (Foster et al., 1982; Waxman et al., 1989; Rasband et al., 1999) when only Nav1.2 is present, suggests that the expression of Nav1.2 channels may serve to support conduction of action potentials in demyelinated axons. Thus deployment of Nav1.2 channels along demyeli-nated axons may serve an adaptive function. Nonetheless, the ability of Nav1.2 to sustain high-frequency conduction may be limited, and the sensitivity of Nav1.2 channels to small, slow depolarizations may contribute to ectopic firing or unstable patterns of firing after demyelination.

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